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Metabolic and Pharmaceutical Aspects of Fluorinated Compounds

Cite this: J. Med. Chem. 2020, 63, 12, 6315–6386
Publication Date (Web):March 17, 2020
https://doi.org/10.1021/acs.jmedchem.9b01877
Copyright © 2020 American Chemical Society
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Abstract

The applications of fluorine in drug design continue to expand, facilitated by an improved understanding of its effects on physicochemical properties and the development of synthetic methodologies that are providing access to new fluorinated motifs. In turn, studies of fluorinated molecules are providing deeper insights into the effects of fluorine on metabolic pathways, distribution, and disposition. Despite the high strength of the C–F bond, the departure of fluoride from metabolic intermediates can be facile. This reactivity has been leveraged in the design of mechanism-based enzyme inhibitors and has influenced the metabolic fate of fluorinated compounds. In this Perspective, we summarize the literature associated with the metabolism of fluorinated molecules, focusing on examples where the presence of fluorine influences the metabolic profile. These studies have revealed potentially problematic outcomes with some fluorinated motifs and are enhancing our understanding of how fluorine should be deployed.

SPECIAL ISSUE

This article is part of the Drug Metabolism and Toxicology special issue.

Introduction

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The inclusion of fluorine in drugs, drug candidates, and agricultural chemicals continues to grow, a trend that is being driven by a deeper understanding of this remarkable element and its effects on molecular properties and biological activity.(1−14) The first fluorinated drug was introduced in 1955, and with the exceptions of 1960–1969 and 2000–2009, the presence of fluorine in approved drugs has increased every decade since, as summarized by the statistics presented in Figure 1. Many new synthetic methods to install fluorine have been developed over the last 15 years, providing access to a range of interesting and potentially useful fluorinated motifs.(15−20) The frequent use of fluorine in both drug and agricultural chemical design is also a function of its wide ranging effects on molecular properties.(1−5,9−12) Patterns of fluorination can enhance potency and/or specificity, increase membrane permeability, modulate metabolism, moderate the pKa of proximal functionalities, influence conformation, stabilize inherently reactive functionalities, and create higher-order bioisosteres that offer advantages, all of which are dependent on context.(1−8,21,22) In turn, studies of the metabolism and disposition of fluorinated compounds have advanced our knowledge and understanding of metabolic pathways. These efforts have not only provided insight into why fluorine can be advantageous but also identified structural arrangements that can present cryptic liabilities.(21,23) In this Perspective, we provide a survey of the metabolism of fluorinated compounds and capture observations that highlight potentially problematic structural arrangements.

Figure 1

Figure 1. Fluorine-containing drugs approved by the U.S. Food and Drug Administration through the end of 2019.

A common application of fluorinated motifs in drug design is to confer enhanced metabolic stability or influence the metabolism of a molecule. This application takes advantage of both the small size of the fluorine atom, which falls between that of a hydrogen atom and an oxygen atom, and the strength of the carbon–fluorine bond, which, at 98–115 kcal/mol, is the strongest of all of the common carbon–heteroatom bonds.(24) By comparison, C–H bonds (89–110 kcal/mol), C–Cl bonds (74–97 kcal/mol), and C–CH3 bonds (77–101 kcal/mol) are of lower strength.(25) However, while the C–F bond is strong and fluorine itself is a relatively poor leaving group (Table 1), there are many circumstances in which fluorine is not chemically inert.(26,27) This observation extends to alkyl, alkenyl, and aryl fluorides and encompasses mono-, di-, and trifluorinated substituents, which can be intrinsically chemically reactive or activated during metabolism. As an example, (S)-γ-fluoroleucine (1) readily cyclizes to the lactone 2 with the expulsion of fluoride (Scheme 1), which is remarkable since the fluorine is bound to a quaternary center and the carboxylate moiety is a relatively poor nucleophile. This reaction leads to significant chemical degradation of 1 in vivo, which limits the potential of the [18F] isotope to be used as a tracer for positron emission tomography (PET) studies of tumors.(28) As another example of this phenomenon, (S)-γ-fluoroleucine derivative 3, a synthetic precursor of the cathepsin K inhibitor odanacatib (4), must be stored at 4 °C to prevent the occurrence of a similar cyclization.(29,30) Fluorinated motifs that are converted enzymatically to intermediates that expel fluoride have been exploited in the design of mechanism-based inhibitors (MBIs) of enzymes, while the metabolism of a fluorinated molecule can set the stage for the elimination of fluoride, leading to the generation of electrophilic products that may react with biological nucleophiles.(31) Moreover, the metabolism of fluorinated compounds can be extensive, with processing through multiple consecutive steps that can culminate in the release of low-molecular-weight and structurally simple fluorinated toxins.
Table 1. Relative Rates of Reaction of 1-Halo-3-methylbutanes with NaOMe in MeOH to Afford 1-Methoxy-3-methylbutane(7)
Xrelative rate of reaction
F1
Cl71
Br3500
I4500

Scheme 1

Scheme 1. (S)-γ-Fluoroleucine (1) Converts Spontaneously to Amino Lactone 2 with Loss of HF

1. Fluoroacetic Acid and Other Small Fluorinated Compounds as Toxins and Metabolic Byproducts

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1.1. Fluoroacetic Acid Biosynthesis

Fluoroacetic acid (5) is an elementary fluorinated compound that is profoundly toxic in vivo and can be produced by several metabolic pathways from precursors 612′ (Figure 2). Accordingly, there are documented examples in which the release of 5 or a precursor during the metabolism of a fluorinated drug candidate has presented toxicological problems. First synthesized in 1896, 5 was subsequently discovered to occur naturally in plants and bacteria.(32,33) The biosynthetic pathway leading to 5 is captured in Scheme 2, with the fluorinase-dependent conversion of S-adenosylmethionine (13) to 5′-fluoro-5′-deoxyadenosine (14) representing the key step in forging the carbon–fluorine bond.(34) Theoretical studies suggest that the fluorinase enzyme reduces the barrier to C–F bond formation by 9.3–11.7 kcal/mol and chaperones the poorly nucleophilic, basic fluoride toward attack onto C-5′ of the ribose of S-adenosylmethionine.(35) This process is favored kinetically over attack onto the other two possible carbon atoms, whereas deprotonation to afford a sulfur ylide is calculated to be thermodynamically unfavorable.(36−38) The binding of fluoride to the enzyme is believed to precede the binding of S-adenosylmethionine. The reaction has been modeled to proceed by an SN2 process that entails a formal inversion of configuration at C-5′, although the proposed trajectory has fluoride approaching at a slightly suboptimal 164° angle of attack.(37) Hydrogen-bonding interactions between fluoride and the backbone N–H and side-chain O–H groups of Ser158 and Thr80 compensate for the penalty associated with desolvating fluoride from its aqueous environment.(37) The ribose moiety is held in place by additional hydrogen-bonding interactions between the 2′,3′-diol moiety and Asp16, the side chain N–H of Trp50, and the backbone N–H of Tyr77, all of which help to constrain the furan ring.(36−38) The release of 5 from 14 follows a pathway that is initiated by exchange of the adenine base for phosphate, a process catalyzed by purine nucleoside phosphorylase, to provide 5-fluoro-5-deoxy-d-ribose-1-phosphate (15). Phosphate 15 is converted to acyclic 16 by an isomerase, and an aldolase converts 16 to 17 via a retro-aldol reaction. This step results in the concomitant release of fluoroacetaldehyde (6), which is oxidized by aldehyde dehydrogenase (ADH) to complete the synthesis of 5. A pyridoxal 5′-phosphate (PLP)-dependent transaldolase uses l-threonine as a substrate to exchange 6 for a molecule of acetaldehyde, producing 4-fluorothreonine (18) as the only other known naturally occurring fluorinated compound.(39) Additionally, fluorinated uracils have been isolated from marine sponges, but these compounds may have accumulated due to exposure to an industrial effluent.(36,40)

Figure 2

Figure 2. Fluoroacetic acid (5) and known metabolic precursors 612.

Scheme 2

Scheme 2. Biosynthesis of 5 and 18 and (Inset) Details of the Transition State as Proposed by Theoretical, Structural, and Kinetic Studies

1.2. Fluoroacetic Acid Toxicity

Fluoroacetic acid (5) is toxic to mammals, with the lethal dose in humans ranging from 2 to 10 mg/kg. Rats (0.1–5 mg/kg) and dogs (0.05 mg/kg) are incrementally more sensitive.(41) As a consequence, the sodium salt of 5 (also known as “Compound 1080”) is used as a rodenticide.(42) The toxicity associated with 5 is fully recapitulated by the aldehyde 6, the methyl (7), propyl (8), and isopropyl (9) esters, the primary amide 10, and 2-fluoroethanol (11) (Figure 2). These observations are consistent with the notion that these molecules act as prodrugs of 5 in vivo.(43) 2-Fluoroethyl 2-fluoroacetate (12) is twice as toxic as 5, reflecting the dual source of the toxin from this ester.
The toxicity of 5 is caused by its entry into the Krebs cycle and conversion to a potent inhibitor of the enzyme aconitase.(41,44) The normal function of aconitase is to convert citric acid (19) to isocitric acid (21) by the pathway outlined in Scheme 3A. The initial step is the dehydration of 19 to afford cis-aconitate (20), which is believed to flip in the active site of the enzyme to set the stage for the addition of H2O to deliver 21.(44) However, aconitase also catalyzes the dehydration of (−)-erythro-(2R,3R)-2-fluorocitric acid (24) in a manner that is analogous to its dehydration of the natural substrate (Scheme 3B). Remarkably, the Claisen condensation catalyzed by citrate synthase between 22, the CoA ester of 5, and 2-oxosuccinic acid (23) produces only 24 and none of the other three possible diastereomers. Hydration of the olefin of 25 by aconitase is usurped when the addition of H2O precipitates an SN2′-like process that ejects the allylic fluoride, generating 4-hydroxy-trans-aconitate (26), a potent but reversible and tight-binding inhibitor of aconitase (Scheme 3B).(41,44,45) Turnover of 24 by aconitase produces a single molecule of fluoride per enzyme, indicative of efficient enzymatic inactivation.

Scheme 3

Scheme 3. Biochemical Reactions of Native and Fluorinated Substrates Catalyzed by Aconitasea

a(A) Dehydration of citric acid (19) to form 20 is followed by rehydration to give isocitric acid (21). (B) Compound 5 is converted to fluoroacetyl-CoA (22), which reacts by a Claisen condensation with 23 to give (−)-erythro-(2R,3R)-2-fluorocitric acid (24) in a stereospecific manner. Dehydration of 24 to give 25 is followed by a flip in the active site as a prelude to the addition of H2O. This addition produces 4-hydroxy-trans-aconitate (26), a potent and tight-binding inhibitor of aconitase that represents the ultimate toxicant produced by the biochemical transformation of 5.

Interestingly, aconitase also accepts (+)-erythro-(2R,3R)-2-fluorocitric acid (27) as a substrate but continues to produce fluoride so long as this substrate remains available.(41,44) The explanation for this finding invokes the binding of 27 to aconitase with an orientation that is the reverse of 24, thereby producing 28 (Scheme 4). A flip of 28 in the active site followed by hydration affords the fluorohydrin 29, which eliminates HF and degrades to oxalosuccinic acid (30). Decarboxylation of 30 produces α-ketoglutaric acid (31), completing a biochemical sequence in which no strong inhibitors of aconitase are formed.

Scheme 4

Scheme 4. Metabolism of (+)-erythro-(2S,3S)-2-Fluorocitric Acid (27) by Aconitasea

a(+)-erythro-(2S,3S)-2-Fluorocitric acid (27) is subject to elimination of H2O to afford 28, which flips in the enzyme active site to set the stage for the addition of H2O to produce 29. This compound collapses with loss of HF to give oxalosuccinic acid (30), which decarboxylates to afford α-ketoglutaric acid (31).

Many of the features of poisoning by 5 include direct and indirect consequences of impaired oxidative metabolism. Energy production is reduced, and intermediates of the Krebs cycle subsequent to 19 are depleted.(41,46) Concomitantly, the inactivation of aconitase leads to a rapid elevation of the levels of 19 in blood. The symptoms of poisoning associated with 5, including nausea, vomiting, abdominal pain, sweating, apprehension, confusion, and agitation, are exacerbated by the accumulation of 19 in tissues and typically occur within an hour of ingestion. These symptoms are accompanied by multiple neurological, metabolic, and respiratory disturbances that are eventually fatal.(41,47) (−)-erythro-(2R,3R)-2-Fluorocitric acid (24) is also an irreversible inhibitor of the mitochondrial citric acid transport protein by a mechanism that involves covalent modification of two protein fractions that are associated with the mitoplast of liver, kidney, brain, and heart tissue.(48) This covalent reaction does not involve the loss of fluoride and is catalyzed by an enzyme in a Mn2+-dependent fashion. The protein can be released by treatment with hydroxylamine in a reaction process that produces the hydroxamic acid derivative of 24.(48)

1.3. Metabolism and Release of Fluoroacetic Acid

1,3-Difluoro-2-propanol (32) is also used as a rodenticide. The symptoms of poisoning mimic those of 5, although there is a lag time for the onset attributed to the requirement for metabolism through several steps to release the toxin. Initially 32 is converted to 1,3-difluoroacetone (33) by alcohol dehydrogenase (ALDH), a metabolic step that can be inhibited by 4-methylpyrazole. Both 32 and 33 are metabolized to 24 in rats, although the metabolic pathway that has been proposed for this reaction is mechanistically unsatisfactory since it fails to account for the extrusion of a carbon atom of 33 in a way that is chemically feasible.(49)Scheme 5 suggests an alternative mechanism that invokes a Baeyer–Villiger-type process to generate fluoromethyl 2-fluoroacetic acid (12′) as an intermediate, an apparently unknown compound that can function as a precursor to 5 and then 22.(49−55) While the enzyme that catalyzes this reaction is also unknown, both flavin-containing monooxygenase 5 (FMO5) and the hydroperoxy form of P450 enzymes are known to catalyze similar oxidative rearrangements.(56−59) Hydrolytic cleavage of 12′ leads presumably to the release of formaldehyde and fluoride.

Scheme 5

Scheme 5. Potential Mechanism for the Metabolic Activation of 1,3-Difluoro-2-propanol (32) to Form Fluoroacetic Acid CoA Estera

aThis process is hypothesized to proceed via oxidation of 32 by ALDH to give 1,3-difluoroacetone (33) followed by a Baeyer–Villiger-type process to generate ester 12′. This ester would be anticipated to convert readily to 5 by hydrolysis or otherwise undergo esterase-mediated cleavage to release 5, formaldehyde, and fluoride.

There have been several incidents during drug discovery campaigns where the metabolism of a compound resulted in the formation of 5 and produced toxicity and mortality in preclinical species.(60,61) For example, in a series of kinesin spindle protein (KSP) inhibitors explored for their potential to treat taxane-refractory solid tumors, moderating the basicity of the piperidine ring to a target pKa range of 6.5 to 8.0 was an important parameter to reduce efflux by P-glycoprotein (P-gp) in tumor cells (Figure 3).(60) Addressing P-gp efflux was a focus of this project, and this was assessed by screening compounds in cell lines that either overexpressed or did not express P-gp and defining the resulting ratio of EC50 values as the multidrug resistance protein 1 (MDR) ratio. The calculated MDR ratio for the methylated piperidine 34 was 21.2, well beyond the targeted ratio of 10 (Figure 3). The N-2-fluoroethyl derivative 35 provided the targeted control of piperidine basicity, whereas the less basic difluoroethyl homologue 36 did not. However, 35 was acutely toxic to rats following oral administration at a dose of 12 mg/kg. The identification of the N-dealkylated piperidine 37 as the major metabolite in rat liver microsomes (RLM) and hepatocytes led to the suggestion that the release of 6 would provide a metabolic precursor to 5, believed to be the ultimate toxicant (Scheme 6).(60) This problem was circumvented by installation of the fluorine atom within the piperidine ring, where the effect on the pKa of the heterocyclic N atom was dependent on whether the fluorine was oriented axially or equatorially. The axial isomer 39 (MK-0731) was 1.2 log10 units less basic than the equatorial isomer 38, with the former offering the preferred profile and being selected for a phase I clinical trial.(60)

Figure 3

Figure 3. Example of the tactical deployment of fluorine to modulate the basicity in piperidine-based KSP inhibitors.

Scheme 6

Scheme 6. Major Metabolic Pathway for 35 in RLM and Hepatocytes
The peptide-based fluoromethyl ketone Z-Phe-Ala-CH2F (40) offers another example of the metabolic release of 5.(61) This compound was designed as an MBI of cysteine proteases and examined as a potential treatment for osteoarthritis. Both oral and intravenous administration of 40 to rodents produced 5 in the heart, liver, and kidney.(61) Notably, following oral administration of 40 at 100 mg/kg, the concentrations of 5 in these tissues reached toxic levels of 0.2 to 0.9 μg/g of tissue. While a mechanistic explanation for the release of 5 from 40 was not offered, a Baeyer–Villiger rearrangement catalyzed by an FMO or a P450 enzyme may be responsible, as suggested by the mechanism presented in Scheme 7.(54,56) The initial addition reaction is facilitated by the electron-withdrawing fluorine substituent and involves the addition of a peroxy moiety, which is a known intermediate in the P450 catalytic cycle.(62) This moiety attacks the electrophilic carbonyl to afford an intermediate that rearranges to ester 41. Hydrolysis of 41 by esterases or peptidases in tissues would release 5 and the unstable aminal 42, which would collapse to acetaldehyde (43) and the amide Cbz-Phe-NH2 (44). The teaching in this example is that mono-α-fluoromethyl ketone derivatives should be deployed with caution, with additional steps taken to ensure that 5 is not liberated as the result of metabolism. In particular, it may be inadequate to address this concern by performing broad metabolite profiling studies using liquid chromatography and electrospray mass spectrometry (LC–MS), since 5 has a low molecular weight (78 Da) and could be easily overlooked using these methods. Hence, drug candidates containing this motif may require a targeted approach to measure the extent of 5 released in vivo. Such an approach would be warranted, for example, in the case of the autophagin-1 (ATG4B) inhibitor 45, which is believed to alkylate the catalytic cysteine (Cys74) of the enzyme to afford 46 by the mechanism illustrated in Scheme 8.(63−65)

Scheme 7

Scheme 7. Enzymatic Baeyer–Villiger Oxidation of Z-Phe-Ala-CH2F (40)

Scheme 8

Scheme 8. Covalent Inhibition of ATG4B by the Fluorinated Peptide Mimetic 45 to Afford Alkylated Enzyme 46
An [18F]-substituted PET tracer designed to image the cannabinoid receptor subtype 2 (CB2) in the central nervous system (CNS) was prepared from a series of carbazole-based ligands, with 47demonstrating high affinity for the CB2 receptor and good selectivity over the CB1 subtype.(66) However, this tracer was metabolized rapidly in mice, with oxidative N-dealkylation postulated as one of the main metabolic pathways, raising a safety concern over the potential liberation of 6 and its subsequent oxidation to 5.(66) On the basis of these observations, a series of analogues with expanded fluoroalkyl moieties were synthesized and evaluated. The additional CH3 substituent in the side chain of 48 shielded the carbazole N atom from metabolism by P450 while retaining the high CB2/CB1 selectivity associated with 47. The extent of oxidative N-dealkylation of 48 in liver microsomes was reduced by two-thirds compared with 47, translating to improved exposure in vivo.(66) However, the N-dealkylation of 48 would release fluoroacetone, a compound that produces toxicity in vivo similar to that of 5. Presumably, this effect is a function of metabolism to methyl 2-fluoroacetate (7) via a Baeyer–Villiger-type process, as proposed for 1,3-difluoropropan-2-one (33) (Scheme 5).(67,68)
The anticancer drug 5-fluorouracil (49) was metabolized to 5 in rats following intraperitoneal (ip) administration (180 mg/kg) and in isolated perfused rat livers at exposures of 15 and 45 mg/kg (Scheme 9).(69) Specifically, 19F NMR analysis revealed the presence of 5 in the urine of rats (0.003% of the dose) and in the liver perfusate (0.03 to 0.1% of substrate concentration), in addition to other metabolites of 49. Perfusion of rat liver with α-fluoro-β-alanine (52), a known metabolite of 49, also produced 5 in the perfusate (0.07% of the substrate concentration), a finding that helped to confirm the complex catabolic pathway from 49 to 5 shown in Scheme 9. These results were recapitulated in patients treated with 49, whose urine contained 5 among other fluorinated metabolites.(70) Capecitabine (Xeloda, 59), an oral prodrug of 49 that demonstrates enhanced tumor selectivity, follows an activation pathway that involves unmasking by way of the metabolites 60 and 61 to form 49 preferentially in tumor tissues (Scheme 10).(71) By means of 19F NMR spectroscopy, low amounts of 5 were detected in the urine samples of patients treated with 59.(72) In human urine, the combination of 51 and 52 represented 50% of the administered dose, which is typically 150 or 500 mg. These observations have implicated the release of 5 in the cardiotoxicity and neurotoxicity associated with the clinical use of 49. The pathway summarized in Scheme 9 depends on the reduction of 49 by dihydropyrimidine dehydrogenase to give 50, which is subject to hydrolytic decomposition to afford first the urea 51 and then the amine 52. Oxidative deamination of 52 provides 53, which may either decarboxylate to give intermediate 6 or undergo oxidation to give 54. Both of these intermediates can then be converted directly to 5. It is instructive to note that on the basis of the metabolic pathway outlined in Scheme 9, the carbon atom of 49 that is incorporated into 6 may be derived not only from the C-4 carbonyl moiety but also prospectively from C-6.

Scheme 9

Scheme 9. Biotransformation of 49a

a(a) 5-Fluorouracil (49) is a substrate of both orotate phosphoribosyl transferase, which catalyzes the addition of a phosphorylated ribose moiety to yield 55, and dihydropyrimidine dehydrogenase, which carries out the initial step in the catabolic pathway that mediates the disposition of the drug. (b) The triphosphate metabolite 56 may be incorporated into DNA, leading to downstream single-strand breaks. (c) The monophosphate 57 reacts with thymidylate synthase and 5,10-methylene tetrahydrofolate, forming the covalent inactivated enzyme complex 58. (d) The multistep catabolic sequence proceeds through a postulated carbon–carbon bond cleavage and decarboxylation, culminating in the formation of 5, in which the acid group may be derived from either C-4 or C-6 of the starting material.

Scheme 10

Scheme 10. Metabolism of Capecitabine (59) to 49
Alternatively, 49 may enter the nucleotide biosynthesis pathway, generating a host of intermediates, including 55 en route to 56. Triphosphate 56 can either be incorporated into DNA or successively dephosphorylated to afford the monophosphate 57, which is a covalent inactivator of thymidylate synthase.(73) Inhibition of this enzyme involves nucleophilic attack by the catalytic cysteine residue onto C-6 of 57, mimicking the Michael addition process that occurs with the natural substrate. However, the presence of the fluorine atom usurps the normal process of methylation and leads to the stable covalent complex 58. The incorporation of 56 into DNA and the covalent modification of thymidylate synthase are two of the mechanisms by which 49 exerts its pharmacological activity.
Another example of a metabolic pathway leading to the inadvertent production of fluoroacetic acid was documented during the development of the hepatitis C virus (HCV) NS4B inhibitors 6265 illustrated in Figure 4.(74,75) Safety evaluation of the lead HCV inhibitors 62 and 63 in rats revealed two problems associated with metabolic modification: N-dealkylation of the sulfonamide with presumed release of 1,3-difluoroacetone (33), a metabolic precursor to 5 (Scheme 5), and oxidative metabolism of the indole ring leading to several glutathione (GSH) conjugates that accounted for approximately 20% of the administered dose. In the design of the subsequent compound 64, installation of a fluorine substituent at C-5 of the indole attenuated metabolism of the heterocycle, while modification of the sulfonamide moiety addressed the release of 33. In the rat, 64 was metabolized primarily by N-dealkylation of the primary sulfonamide, releasing trifluoromethyl acetone, which was detected in plasma and bile. Additionally, a single GSH conjugate that amounted to <2.5% of the dose administered was formed, reflecting the influence of the indole 5-fluoro substituent. While this compound represented an improvement over 62, it was characterized by a long half-life in both the dog (149 h) and monkey (22 h), necessitating additional modification that led to the identification of 65. This compound exhibited more reasonable half-lives in the rat, dog, and monkey (7.5 to 8.9 h) and was selected for clinical evaluation.(75) The major metabolites derived from 65 in vivo were the result of benzylic oxidation and N-dealkylation of the sulfonamide.

Figure 4

Figure 4. Optimization of HCV NS4B inhibitors to avoid the production of 33, a metabolic precursor to 5.

1.4. Other Simple Fluorinated Compounds and Their Homologues

To understand how fluorine substitution alters the toxicology of small fluorinated aldehydes and acids, the effects of non-halogenated compounds are worth considering as a basis for comparison. Humans are exposed to acetaldehyde by the inhalation of tobacco smoke and emissions from industrial sources as well as from the consumption of ethanol. Acute and subacute inhalation of acetaldehyde in rats caused dose-dependent degenerative hyperplastic and metaplastic changes in the epithelium of the upper respiratory tract, accompanied by growth retardation and hematological changes.(76) In a chronic inhalation study, rats developed squamous cell carcinomas in the respiratory epithelium and adenocarcinomas in the olfactory epithelium.(77,78) Chronic consumption of alcohol led to the excessive hepatic disposition of acetaldehyde, an oxidative metabolite of ethanol and a culprit in the development of alcoholic liver diseases and hepatocellular carcinoma.(79) To some extent, acetaldehyde may be detoxified via conjugation with cysteinylglycine in vivo.(80) Acetaldehyde initiates mutagenic events by direct interactions with DNA and promotes tumor progression through various mechanisms, including elevated oxidative stress, damage to DNA repair mechanisms, and the formation of protein adducts that may elicit an immune response. On the other hand, acetic acid is a common chemical intermediate in the manufacture of organic compounds, insecticides, and food additives. It causes acute corrosion of the mucous membranes of the respiratory and gastrointestinal tracts through inhalation and ingestion, respectively, and dermal irritation through local absorption.(81) Acetic acid was not genotoxic in the Ames test or in the SOS chromotest,(82) and while it caused concentration-dependent chromosomal aberrations in Chinese hamster ovary K1 cells, this effect was ascribed to the reduced pH of the culture medium.(83) Interestingly, acetic acid also expedited cancer progression in a papilloma-bearing mouse model.(84)
While fluoroacetic acid (5) is toxic because of its facile entry into the Krebs cycle, the higher homologues difluoroacetic acid (66) and trifluoroacetic acid (67) presented different toxicological profiles in vivo.(85−89) Analogous to the production of 5 in vivo, 66 and 67 are potential byproducts that may be formed during oxidative or hydrolytic metabolism of small-molecule drug candidates. However, there are fewer reports of toxicity associated with these carboxylic acids. Developmental toxicological studies on the haloacetic acids 66, 67, and 68 using 3-6 somite staged CD-1 mouse embryo cultures revealed dysmorphogenesis after 24 h of exposure.(85,86) The observed effects on neural tube development ranged from prosencephalic hypoplasia to nonclosure defects throughout the cranial region. Exposure to 6668 also affected optic development, produced malpositioned and/or hypoplastic pharyngeal arches, and perturbed heart development. In order to determine the relative toxicities of these agents, benchmark concentrations were calculated as the lower 95% confidence interval of the concentration that produced a 5% increase in neural tube defects. The benchmark concentrations occurred over a wide range, with 66 the least toxic (5912 μM), 67 (3652 μM) and 5 (692 μM) incrementally more problematic, and 68 (2.7 μM) the most toxic. Interestingly, the chlorinated acids 69 (2452 μM) and 70 (1336 μM) disrupted development in vivo but were among the least toxic in vitro.
The production of trifluoroacetaldehyde (71) in vivo as a metabolic intermediate was associated with testicular toxicity and was thought to be responsible for the lesion produced following the administration of trifluoroethanol (72).(87,88) In the rat, the damage to spermatogonia and spermatocytes following a single dose of 72 (25 mg/kg ip) was apparent within 8 h. The lesion was first observed during the late pachytene stage of spermatogenesis. Interestingly, 71 and 72 were more potent toxins in vivo than 67, which produced the same lesion but only at higher doses.(87) The metabolism and toxicity of 72 in rats was described previously.(88) Deuterated 72 was less toxic (LD50 = 0.44 g/kg) than 72 (LD50 = 0.21 g/kg), reflecting its 4.2-fold lower intrinsic clearance (Vmax/Km) in liver microsomes, a process that involves the oxidation of the alcohol to the aldehyde. In contrast, deuteration of 71 did not affect either its lethality or rate of metabolism.
N-Trifluoroethyl moieties can be N-dealkylated by P450 enzymes in vivo to release 71, as demonstrated by studies with piperidine derivatives based on 73 (Scheme 11; it should be noted that the full structures of the substrates were not disclosed).(89) Following administration of 73 to rats, testicular toxicosis was apparent. The toxicological effects correlated with exposure to 71 and targeted both the epididymis, which became filled with cellular debris, and the spermatocytes, which experienced necrosis.(89) A similar safety study performed with the N-tetrazolyl analogue 75 revealed no evidence of testicular injury, providing further support for the role of 71 in the development of the testicular lesion.(89) This observation heightens concern for the formation of 71 during the metabolism of O- and S-trifluoroethylated compounds.

Scheme 11

Scheme 11. Compounds Containing N-Trifluoroethyl Groups May Be Metabolized In Vivo to Release 71, Which Causes Testicular Toxicity
Finally, fluoride itself is known to carry both benefits and risks.(90,91) On the one hand, fluoride is used widely in dental health for the prevention of tooth decay (dental caries or cavities). Fluoridated water (approximately 0.5 to 0.7 mg/L fluoride) and fluoride-containing toothpaste (approximately 1000 to 2000 ppm) and mouth rinses (approximately 0.05% or 225 ppm) are all effective fluoride supplements that are used for this purpose. On the other hand, the distribution of fluoride into tissue is thought to be nonsaturable, and long-term exposure to abundant sources of fluoride can lead to health problems. Many of the consequences of excessive fluoride exposure are also irreversible. Since fluoride distributes into bones, dental fluorosis provides an early indication of chronic fluoride toxicity. This condition is characterized by hypomineralization, increased porosity of surface enamel, and tooth discoloration and damage. Severe chronic fluorosis is also manifested in the skeleton, where increased bone density and abnormal bone outgrowths are observed. Clinical symptoms of skeletal fluorosis may include joint stiffness and pain, deformities in the joints and spine, and neurological problems. Crippling skeletal fluorosis is rare and associated with intake of highly fluoridated water (greater than 10 mg/L). Such effects can also arise in connection with metabolic release of fluoride from drugs that are administered at high doses (vide infra).

1.5. Defluorinating Enzymes

Halogenases with the capacity to defluorinate 5 have been characterized in bacteria, plants, and several mammalian species.(92−95) The mammalian and bacterial enzymes employ an Asp-His-Asp catalytic triad in which one of the Asp residues acts as a nucleophile to displace the fluoride by an SN2-type mechanism. Two proximal arginine residues stabilize the negative charge on the carboxylic acid of 5. The departure of fluoride is facilitated by the side chains of proximal Tyr, Trp, and His residues that are believed to lower the activation barrier for fluoride release via hydrogen-bonding interactions (Scheme 12). The subsequent hydrolysis of the aspartate ester releases glycolic acid and restores the enzyme to its native state.(93−99) The architecture of this halide pocket confers specificity for fluoride over chloride, such that chloroacetic acid is processed more slowly.

Scheme 12

Scheme 12. Mechanism of Defluorination of 5 by Mammalian and Bacterial Defluorinase Enzymes
Some mammalian defluorinase activity has been found to depend on GSH, leading to the suggestion that this enzyme may be a glutathione S-transferase (GST).(92,100) Available evidence indicates that GST zeta (GSTZ) is involved in catalyzing the dehalogenation of some α-haloacids.(100) However, the rate of conversion of 5 to S-(carboxymethyl)glutathione (76) by GSTZ was relatively low (172 nmol min–1 (mg of protein)−1). Higher rates of catalysis were measured with other substrates, including racemic 2-chloropropionic acid (1655 nmol min–1 (mg of protein)−1), 2-bromopropionic acid (2142 nmol min–1 (mg of protein)−1), and 2-iodopropionic acid (2532 nmol min–1 (mg of protein)−1). Similar findings were obtained in another study that found GSTZ1C to be the only GST isoform to possess catalytic activity to release fluoride from 5, although the rate of catalysis (210 nmol min–1 (mg of protein)−1) was lower than for other model substrates, including dichloroacetic acid (69) and chlorofluoroacetic acid (77).(92) The defluorination activity resided mainly in the cytosolic fraction of rat liver and was inhibited noncompetitively by 1-chloro-2,4-dinitrobenzene. Interestingly, this study found GSTZ1 to account for only 3% of all of the defluorination activity toward 5 in rat cytosol; thus, GSTZ1 appears to contribute marginally to the overall detoxification of 5.(92)
While the role of mammalian GSTs in the defluorination of 5 has been suggested, there is evidence for the involvement of other enzymes as well. One study indicated that the defluorinase activity present in mouse liver cytosol did not bind to a GSH affinity column, a tool used widely for the separation of GST isozymes.(101) Protein chromatofocusing and immunoprecipitation studies also indicated that the defluorinase activity was clearly distinct from GST isozymes. This enzyme preparation catalyzed the defluorination of fluoroacetamide 10 as well as acid 5, although the rate of the former reaction was approximately 10-fold lower. A similar difference in the rate of defluorination between acid 5 and amide 10 was observed when crude rat and mouse liver supernatants were used.(102)
The fate of 5 in rodents was investigated alongside a series of analogues of 5, which were administered ip at doses ranging from 2 to 5 mg/kg together with appropriate antidotes.(103)19F NMR spectra of urine and kidney samples collected from these animals revealed the presence of fluoride. Following administration of isotopically labeled derivatives of 5, a number of conjugates related to 76 and their sulfoxidation products 79 were observed in urine as a result of fluorine displacement, whereas 76 and a proposed acyl glucuronide of 5 were detected in bile. The formation of 76 and fluoride, along with (−)-erythro-(2R,3R)-2-fluorocitric acid (24), were also observed following incubation of 5 in mouse liver cytosol.(103)
Fluoroacetamide (10) and 2-fluoroethanol (11) are both converted to 5 and therefore share some of the same downstream products of metabolism. After ip administration of 10 to rodents, 19F NMR spectra revealed the presence of 2-fluoro-N-hydroxyacetamide (78), 24, and fluoride in tissue and excreta.(103) Administration of 11 to rodents resulted in its conversion to fluoroacetaldehyde (6), which was also detected in the liver microsomal fraction, and then on to 5 and fluoride, both which were recovered in urine. On the other hand, ip administration of 24 and (+)-erythro-(2R,3R)-2-fluorocitric acid (27) to rats resulted in their excretion mostly intact, with increasing amounts of fluoride evident in urine only after 6 h. The administration of 5 and 24 to rodents also resulted in elevated levels of citric acid (19) and increased glucose and diminished urea concentrations, suggesting disruption of the Krebs cycle and ammonia metabolism that are consistent with their known mechanisms of toxicity. The metabolic pathways of these fluorinated small molecules in rodents are summarized in Scheme 13, which also captures insights gleaned from in vitro experiments to identify the enzyme or subcellular fraction involved in each step.(103)

Scheme 13

Scheme 13. Metabolic Pathways of 5, 10, and 11 in Rodents

2. Fluorinated Alkanes

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2.1. Hydrochlorofluorocarbons and Hydrofluorocarbons

Perhalogenated alkanes or chlorofluorocarbons (CFCs) possess unique chemical and physical properties, rendering them useful as refrigerants, blowing agents, cleaning fluids, and propellants.(104) These CFCs, which contain up to three carbon atoms that are fully substituted with chlorine and fluorine atoms, are each characterized by a low boiling point, a low surface tension and viscosity, a high vapor density, and limited flammability. In addition, they have a low propensity to undergo metabolic activation leading to adverse effects on health. However, their widespread use began to be phased out in the 1990s because of their potential to absorb ultraviolet radiation and photolytically release chlorine into the stratosphere, leading to the depletion of the ozone layer.(104) To avoid these environmental drawbacks, hydrochlorofluorocarbons (HCFCs) were investigated as replacements for CFCs. HCFCs feature C–H bonds that can be oxidized in the troposphere before the molecule rises into the stratosphere.(105) HCFCs are more susceptible to metabolic activation than CFCs, generating reactive intermediates via pathways that may be associated with a variety of pathogenic consequences. In addition, many inhalation anesthetics are HCFCs and are prone to bioactivation. In this section, the biotransformation and downstream adverse effects of the more common HCFCs are summarized.
A P450-mediated oxidative dehalogenation reaction to yield trifluoroacetyl halides is common across several HCFCs, including HCFC-123 (80),(106,107) HCFC-124 (81),(108) and HCFC-125 (82).(105) These HCFCs are characterized by two halogen atoms and a single hydrogen atom bound to the same carbon atom. The rate of production of trifluoroacetic acid (67) has been demonstrated to be tightly correlated with ΔHact, the enthalpy of hydrogen atom abstraction from the carbon atom, with the energetic barrier to abstraction influenced by the number of halogen substituents present and inversely associated with their electronegativities.
HCFCs bearing one halogen and two hydrogen atoms at a single carbon are metabolized differently. Following administration of HCFC-131a (83), HCFC-132b (84), or HCFC-133a (85) to rats, the metabolite profiles in urine varied as a function of the fluorine substitution pattern (Scheme 14).(109,110) P450 catalyzed the initial oxidation of the chloromethyl carbon atom, leading to the release of HCl and the formation of a trihaloaldehyde intermediate. (The potential reproductive effects of trihaloaldehydes have been described previously in the context of trifluoroacetaldehyde (71); vide supra.) This intermediate was then partitioned among three discrete metabolic pathways. The trihaloaldehyde could be oxidized to a trihaloacid or reduced to a 1,1,1-trihaloethanol, which was subject to glucuronidation and sulfation. The halogenated ethanes 83 and 84 were ultimately converted to the carboxylic acids and glucuronidated alcohols, which were observed as the most abundant metabolites, while the sulfate conjugate was produced as a minor metabolite. In contrast, 85 was oxidized to 71, which was readily hydrated or reacted with urea (with or without elimination of water). Release of fluoride from the fluorodihalomethyl group was detected during the metabolism of all three of these halogenated ethane derivatives, although the enzymes responsible were not identified. Additionally, the conversion of 85 to aldehyde 71 in turn produced stable adducts with endogenous nucleophiles that were excreted in urine, as suggested by 19F NMR studies.

Scheme 14

Scheme 14. Metabolic Pathways of HCFCs 8385a

aThe metabolism of 8385 proceeds in each case through an aldehyde intermediate, which is subject to differential metabolism depending on the pattern of halogen substitution (X′, X″, and X‴).

Although HCFCs typically exhibit a favorable acute safety profile, long-term inhalation of HFC-245fa (86) (Scheme 15) led to an increase in the incidence of myocarditis in rats, a rare consequence not observed with other hydrofluorocarbons (HFCs) and likely linked to biotransformation.(111) Studies with 86 revealed a unique C–C bond cleavage reaction as a major metabolic outcome, and certain products formed along the proposed pathway may have the potential to subtend toxicity (Scheme 15).(112) Following inhalation by rats, 86 was oxidized at C-3 by P450 enzymes to afford 1,1,1,3,3-pentafluoro-1-propanol (87), which was excreted in urine. Alternatively, 87 degraded by the elimination of HF to afford the acyl fluoride 88, which was readily hydrolyzed to 3,3,3-trifluoropropanoic acid (89), another urinary metabolite. GC–MS and 19F NMR analyses also suggested the presence of multiple additional minor metabolites, including 1,1,1,3,3-pentafluoro-2-propanol (90), formed via oxidation of C-2, its oxidation product 1,1,1,3,3-pentafluoro-2-propanone (91), and the hydrate 92. Surprisingly, the main product in urine was trifluoroacetic acid (67), which was formed by a pathway that could be fully recapitulated in RLM. The product of C–C scission was proposed to follow from the interaction of 91 with the P450 Fe–hydroperoxy intermediate to afford 93 via a Baeyer–Villiger rearrangement. The ester 93 is a reactive species that can be converted to 67 enzymatically or by simple hydrolytic degradation.(113) Although covalent modification of proteins by reactive acyl fluorides is well-established, 88 was not implicated in the myocarditis induced by 86 because of its low abundance. Moreover, there is little P450 activity in cardiac tissue, and the short half-life of 88 would limit its ability to reach the heart if formed remotely. Other stable metabolites, such as 67 and 90, have been suggested to cause toxicity through distinct mechanisms, although evidence to support these hypotheses is lacking.

Scheme 15

Scheme 15. Metabolism of HFC-245fa (86)

2.1.1. Anesthetics

Halothane (94), an anesthetic implicated in adverse outcomes, including rare but severe hepatic necrosis, represents a classic example of metabolic activation leading to immune-mediated sequela and target organ toxicity.(114−118) In humans, about 80% of 94 was eliminated unchanged, with the remainder being metabolized. As summarized in Scheme 16, P450 enzymes catalyzed two distinct metabolic pathways, one reductive (path a) and the other oxidative (path b), both of which produced chemically reactive intermediates.(119) The oxidative pathway (path b) resulted in hydroxylation of the carbon atom bearing the single hydrogen atom, yielding an unstable halohydrin intermediate that collapsed by elimination of HBr. This reaction produced the highly reactive acid chloride 97, which was readily hydrolyzed to trifluoroacetic acid (67). Following administration of 94 to patients, products of this pathway were detected in urine, with 67 serving as a clinical marker of drug exposure. The reductive pathway (path a) occurred under anaerobic conditions and entailed two steps, the first being one-electron reductive removal of the bromine atom to produce a 1-chloro-2,2,2-trifluoroethyl radical.(120−122) This radical intermediate, which bears some resemblance to the trichloromethyl radical generated during the one-electron reduction of CCl4, was postulated to react with polyunsaturated lipids, leading to the release of 1-chloro-2,2,2-trifluoroethane (95), which was exhaled.(123) Additionally, this radical inactivated P450 enzymes by reaction with FeII in the active site to form an iron−σ-alkyl complex. The second metabolic step was another one-electron reduction of the radical to afford an unstable carbanionic intermediate that decomposed with the loss of fluoride to form 2-chloro-1,1-difluoroethylene (96), which was then exhaled. Studies have suggested that the hepatotoxicity induced by 94 was the result of covalent modification of hepatic proteins, leading to immune-mediated reactions and hepatic necrosis in genetically predisposed subjects upon repeated exposure to the anesthetic. In the most severe cases, this reaction was fatal. While both 97 and the 1-chloro-2,2,2-trifluoroethyl radical may have the capacity to react with nucleophilic cellular macromolecules, several lines of evidence support the involvement of acid chloride 97 in the genesis of immune-mediated toxicity. The first line of evidence was the observation of covalent binding of [14C]-labeled 94 to liver proteins, which resulted in the appearance of neoantigens in experimental animals.(124,125) Second, hepatic proteins in guinea pigs became trifluoroacetylated during exposure to 94.(126−128) Third, serum immunoglobulin G antibodies from patients with hepatitis induced by 94 were found to cross-react with hepatic neoantigens exhibiting the trifluoroacetyl group that were collected from the livers of rats and rabbits exposed to 94.(129) Serum antibodies from the same patients also recognized hepatic neoantigens from patients who died of cardiac failure following anesthesia with 94, whereas serum antibodies from control subjects did not.(130)

Scheme 16

Scheme 16. Metabolic Activation of 94, Which is Metabolized by P450 along (a) Reductive and (b) Oxidative Pathwaysa

a(a) The reductive pathway involves a one-electron reduction with loss of bromine to afford a radical, which either abstracts a hydrogen atom prior to exhalation or is further reduced. The product of reduction is an unstable 1-chloro-2,2,2-trifluoroethyl carbanion intermediate that eliminates fluoride to give 96, which is also exhaled. (b) The oxidative pathway involves oxidation and loss of HBr to give 97, which is readily hydrolyzed to give 67.

Sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane, 98) is a polyfluorinated ether that has been popular as an inhaled anesthetic since 1990 on the basis of its rapid uptake relative to both halothane (94) and isoflurane (99).(131)The rapid elimination of 98 through exhalation and metabolism is governed by its poor aqueous solubility, differentiating it from highly lipid-soluble anesthetics such as methoxyflurane (100). While the majority of the dose of 98 administered to humans was exhaled unchanged, approximately 2–5% underwent oxidation of the fluoromethyl group by CYP2E1, resulting in loss of fluoride to afford the formate ester 101, which was converted to hexafluoroisopropanol (HFIP, 102), as summarized in Scheme 17.(132−134) Replacement of the fluoromethyl H atom with D mitigated the formation of 102, implicating the oxidation of the fluoromethoxy moiety as the rate-limiting step in metabolism. Moreover, pretreatment of rats with EtOH prior to the preparation of liver microsomes resulted in a 3-fold increase in metabolic turnover, confirming the reliance on CYP2E1. Once formed, 102 rapidly formed the glucuronide 103, which was the main metabolite of 98 in urine. Thus, 98 is differentiated from other anesthetics like 94 and 99 by the limited extent of metabolism and the avoidance of any acyl halide products.(135−137)

Scheme 17

Scheme 17. Metabolism of 98
Upon contact with soda lime, which is used to absorb CO2 from breathing gases during general anesthesia, 98 is subject to base-mediated loss of HF to afford the fluorinated olefin 2-(fluoromethoxy)-1,1,3,3,3,-pentafluoro-1-propene (104), which is also known as compound A (Scheme 18).(138,139) In rats, 104 has been shown to cause nephrotoxicity, although this outcome has not been confirmed in human subjects.(139) In rats and humans, 104 was converted by GST to the saturated GSH conjugate 105, a metabolic process analogous to that observed with other fluorinated alkenes (vide infra).(140−142) Alternatively, the GSH conjugate underwent elimination to form the unsaturated GSH conjugate 106. Both conjugates were subject to sequential degradation by processes catalyzed by γ-glutamyltransferase and dipeptidases, generating the corresponding cysteine conjugates 107 and 108, respectively. The cysteine conjugates were substrates for β-lyase, which catalyzed the formation of thiolates 109 and 110. At this point, the metabolic fate of these compounds converged, with 109 losing HF and 110 simply tautomerizing, each affording 111. In the final steps, hydrolysis of 111 gave 112, which degraded further to give trifluorolactic acid (113). The GSH-dependent metabolism of 104 resembled the bioactivation of other fluorinated olefins to nephrotoxic thiolate intermediates. Surprisingly, the nephrotoxicity of 104 was exacerbated by administration of the γ-glutamyltransferase inhibitor acivicin and the β-lyase inhibitor aminooxyacetic acid, calling into question the role of this pathway in the onset of toxicity.(143,144) However, no alternative pathway for the metabolic activation of 98 has been proposed.

Scheme 18

Scheme 18. Metabolism of 104, a Base-Catalyzed Degradation Product of 98, in Rats and Humans

2.2. Drug-like Compounds Featuring Fluorinated and Difluorinated Alkanes

Under physiological conditions, both biologic nucleophiles and drug-metabolizing enzymes can participate in reactions that cleave the C–F bonds of monofluoroalkyl groups to liberate fluoride.(27) Such reactions have been observed in studies of [18F]-labeled PET tracers, since the fate of the radioactive fluoride can be easily tracked. As a PET tracer, the [18F] radionuclide offers certain advantages.(145) First, the radiological half-life (110 min) is comparable to the typical length of the imaging window, minimizing the radiation burden for the patient and enabling repeat imaging on successive days. Second, networks for the distribution of [18F]fluorodeoxyglucose have demonstrated that production of [18F]-labeled radiopharmaceuticals at central sites is a reasonable alternative to on-site production.(146) Thus, the [18F] isotope has become the preferred radionuclide for PET imaging studies. Procedures to install [18F] into organic molecules must proceed rapidly and with high radiochemical yield to be useful, and the number of suitable reactions is increasing.(15−20) One such reaction involves the displacement of a good leaving group by [18F]fluoride at an aliphatic or aromatic position. However, since it is often difficult to incorporate an [18F] label into an aromatic compound in the final synthetic step, the addition of a larger appendage, such as an aromatic ring incorporating a [18F]fluoroalkyl substituent, is used as an alternative approach.(147) To assist in the development of this approach, the fate of fluoroalkyl groups appended to a phenyl ring was examined using human serum and RLM as proxies for stability in vivo.(148) The three homologous 4-(ω-[18F]fluoroalkyl)biphenyls 114, 117, and 121 depicted in Scheme 19 were prepared as model compounds, and all eliminated [18F]fluoride to some degree under the test conditions. In human serum, [18F]fluoroethylbiphenyl 117 and [18F]fluoropropylbiphenyl 121 were relatively stable, with more than 90% remaining after 1 h. In contrast, [18F]-fluoromethylbiphenyl 114 was converted extensively (40 to 50% degraded over 3 h) to [18F]fluoride and the benzylic oxidation product 115, which would convert spontaneously to [1,1′-biphenyl]-4-carbaldehyde (116).(148) Similar trends were observed in RLM, in which 114 suffered from increased reactivity relative to 117 and 121, suggesting that this motif should be avoided for PET imaging studies. Moreover, this degree of chemical reactivity could be interpreted as a safety issue since biologic targets bearing a proximal thiol or other nucleophile may become alkylated, advocating for caution when exploiting electronically activated fluorides.(27)

Scheme 19

Scheme 19. In Vitro Metabolism of a Homologous Series of [18F]fluoroalkylbiphenyl Derivativesa

aBenzylic oxidation of 114 releases fluoride immediately, whereas 117 and 121 require successive benzylic oxidations via the intermediate alcohols 118 and 122, respectively, to afford the ketones 119 and 123. Since the release of fluoride is faster from the intermediate derived from 121 than that from 117, the latter is deemed to have the best overall properties. This compound is oxidized in successive steps to 118 and the α-fluoro ketone 119, which is believed to undergo spontaneous but slow α-elimination (16% over 1 h) to give the corresponding enol. This enol is tautomeric with the ketone 120.

A number of estrogen analogues bearing 11β-(ω-fluoroalkyl) and 11β-(ω-fluoroalkoxy) moieties, represented generically by 125 and 126, respectively, have been explored for their potential to function as PET agents for imaging of estrogen-receptor-positive breast cancers (Figure 5).(149) Most were characterized by selective distribution in female rats, with 10- to 40-fold higher concentrations in the uterus compared with the blood or muscle. The chain length and choice of a carbon or oxygen linkage had implications for both the estrogen receptor binding affinity (improved for 11β-(ω-fluoroalkyl) derivatives 125 compared with the 11β-(ω-fluoroalkoxy) estrogens 126) and the extent of distribution of radioactivity into the bone, which was taken as a proxy for the degree of metabolic defluorination. 11β-(2-Fluoroethoxy)estradiol (128) was the least prone to defluorination, whereas 11β-(2-fluoroethyl)estradiol (127) was the most susceptible.(149) This trend is perhaps surprising since the placement of fluorine in the former molecule does not directly block a site of hydrogen atom abstraction; however, the result does recall a trend observed elsewhere that fluorine substitution at the distal end of a short alkoxy chain can decrease the rate of O-dealkylation.(150) Consistent with this observation, fluorinated alkyl groups have been found to confer protection against oxidation at remote sites.(151)

Figure 5

Figure 5. 11β-Fluoroalkyl and 11β-fluoroalkoxy estrogen derivatives explored for their potential as PET imaging agents.

11C-WAY-100635 (11C-129) has been used to image central serotonin 5-HT1A receptors and monitor serotonin-related neuronal activity (Figure 6).(152,153) However, the installation of the 11C label at the carbonyl carbon of 129 requires a complex synthetic sequence that carries an approximately 10% failure rate. The short radiological half-life of 11C (20 min) also limits the use of 11C-129 to hospitals equipped with an in-house cyclotron and radiopharmacy. In light of these drawbacks, efforts have been made, with mixed success, to identify [18F]-labeled analogues of 129 that could be used as alternatives. One of these compounds, MPPF (130), was characterized by lower 5-HT1A selectivity and lower rat brain uptake, while another, FCWAY (131), underwent defluorination in humans, resulting in PET images of poor quality. PET imaging studies with the three [18F]fluoromethyl bridge-fused ring analogues 133135 demonstrated specific binding to brain regions rich in 5-HT1A receptors in rats.(154) However, these studies also found high rates of radioactivity uptake into bone indicative of defluorination, an outcome that was not forecasted by chemical stability studies using conditions that favored the elimination of HF. Whereas the proclivity of these compounds toward defluorination in vivo would prevent their practical application in human PET imaging, a related compound, [18F]-MEFWAY ([18F]-132), exhibits improved stability in rats and offers continued potential in this area (Figure 6).(155)

Figure 6

Figure 6. Structures of 11C-WAY-100635 (11C-129) and [18F]-derived analogues 130135 explored as potential PET tracers. The asterisk denotes the position of the 11C label in 11C-129.

Vicinal difluorinated alkanes have found infrequent use in drug design, although they exhibit favorable physicochemical attributes and appear to offer a degree of metabolic stability based on studies using Caenorhabditis elegans.(156−158) The oxidation pathways observed in one such study of all-cis polyfluorinated cyclohexane derivatives primarily targeted methylene and benzylic groups that were not substituted by fluorine. The lone exception was observed during the metabolism of ((1R,2S,3R)-2,3-difluorocyclohexyl)benzene (136), which gave rise to the simple hydroxylated derivatives 137139 along with the desfluoro metabolite 140 (Scheme 20).(156) This reaction mechanism was not rationalized and ostensibly involved the oxidation of a remote methylene. The study also noted certain physicochemical trends in this series, including an increase in polarity with increasing fluorination, as measured by a reduction in log P values, and a preference for H2O to associate with the hydrogen-bearing face opposite to that projecting the cis-oriented fluorine atoms. The latter was attributed to the strong polarization of the hydrogen atoms by the adjacent fluorine substituents.(156)

Scheme 20

Scheme 20. Metabolism of ((1R,2S,3R)-2,3-Difluorocyclohexyl)benzene (136) by C. elegansa

aComplete conversion was obtained over 72 h at 28 °C. Compounds 137139 represent the metabolites observed in the study, which included other polyfluorinated substrates in addition to 136. The main site of oxidation was at the benzyic carbon rather than at sites substituted by fluorine. The unexpected formation of 140 was not explained but serves as a reminder that fluorinated alkyl groups may not always be metabolically inert.

The selection of a geminal or vicinal difluorinated alkane in drug design will depend on several factors, including effects on lipophilicity and solubility, properties that are readily calculated in silico.(158) Of particular importance, the molecular volume and the solvation energy of the fluorinated compounds and the overall dipole moment of the fluorinated fragment can be approximated reasonably well by summing the dipole moments of the individual C–F bonds. In this regard, vicinal difluoro groups can be judiciously deployed to help improve drug-like properties.(158) In the preferred gauche conformational arrangement, a vicinal difluoroalkane adopts a F–C–C–F dihedral angle of approximately 70°, which is smaller than the 104° angle adopted by the C–F bonds of a geminal difluoro group. Since the former angle is smaller, the sum of the polarity vectors is longer, resulting in a larger net dipole moment. This increased polarity contributed to an overall effect of increased solubility and reduced lipophilicity for a vicinally difluorinated compound compared with a geminally difluorinated isomer, with no appreciable difference between the molecular volumes of the two compounds.(25,158) This trend was illustrated by the measured properties of the matched pair of difluoroalkyl indoles 141 and 142 as well as by a comparison of the matched pair of hypoxia-inducible factor-2α (HIF2α) inhibitors 143 (PT2385) and 144 (PT2977), both of which were advanced into clinical trials for the treatment of advanced clear cell renal cell carcinoma (Figure 7).(159,160) The metabolite profile of 143 included metabolites formed by oxidative defluorination of the fluorophenyl ring and, separately, glutathione conjugation of the same ring.(159) While no metabolites that represented modifications to the gem-difluoro moiety were identified, 143 suffered from extensive glucuronidation that resulted in suboptimal pharmacokinetics in humans.(159) These shortcomings were corrected by the cis-vic-difluoro isomer 144, which was characterized by decreased lipophilicity, lower protein binding, and attenuated glucuronidation, perhaps as a result of the diminished acidity of the proximal cis-hydroxyl group.(160)

Figure 7

Figure 7. Influence of the pattern of difluorination on the physicochemical properties of the matched pair of indoles 141 and 142 and the HIF2α inhibitors 143 (PT2385) and 144 (PT2977). The solubilities of 141 and 142 were measured in aqueous buffer (pH 6.5), while clearance was measured in human liver microsomes and protein binding of 143 and 144 was measured in human plasma.

The fluorinated allylic position of fluticasone furoate (145) was susceptible to hydroxylation by P450, resulting in the loss of fluorine.(161) While a specific mechanism for the oxidation of 145 has not been proposed, mechanistic studies of the metabolism of the closely related corticosteroid flunisolide (146) (Scheme 21B) suggest the pathway presented in Scheme 21A.(162,163) On the basis of its bound conformation, 145 is primed for 6-β-hydroxylation, since the fluorine substituent occupies the equatorial position and the axial hydrogen is exposed for abstraction by the enzyme.(164) Following rebound of the hydroxyl radical, the fluoroalcohol 147 collapses to the keto intermediate 148, which is conjugated to the 2-carbonyl via the double bond at the 4,5-position. The ketone is then reduced to the observed metabolite 149. While the stereochemistry of the product has not been determined, the corresponding product of flunisolide metabolism that was produced via 150 and 151, 6-OH-desfluoroflunisolide (152), was believed to adopt the R conformation at the site of metabolism (Scheme 21B). Similarly, non-fluorinated steroids like testosterone are hydroxylated on the β face.(165) Thus, the hydroxyl substituent in 152 is installed with the same axial configuration as the hydrogen abstracted from 146.

Scheme 21

Scheme 21. Fluticasone Furoate (145) and Flunisolide (146) Are Both Metabolized by Allylic Oxidation at C-6, Which Results in the Loss of Fluorinea

a(A) Fluticasone furoate (145) undergoes abstraction of the axial 6-hydrogen by P450 with rebound oxidation, leading to 147. This intermediate eliminates fluoride to form the keto compound 148, which is reduced to the 6-hydroxy metabolite 149. While the configuration of 149 has not been determined, analogy to flunisolide (146), which is metabolized in a stereospecific manner (B), would suggest that both steroids likely undergo β-oxidation at this site.

Simpler allylic fluorides lacking the activation afforded by the carbonyl moiety of 145 have also been observed to undergo hydrolytic cleavage of the C–F bond in mouse liver microsomes.(166)

3. Fluorinated Alkenes

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3.1. Volatile Fluorinated Alkenes

Fluorinated alkenes can mimic the topology and physicochemical properties of ketones, esters, and amides (Figure 8a) and carbonyls (Figure 8b), providing improved metabolic stability and potency.(1−3) The fluoroalkene retains features of the amide bond of peptides, including bond length, bond angle, and a significant dipole moment, while permitting either an E or Z configuration. Additionally, the electronegativity of fluorine imbues the alkene with electronic properties that are similar to those of the carbonyl group with respect to dipole moment, charge distribution, and electrostatic potential. Hence, the replacement of amides by fluoroalkenes offers certain advantages, such as resistance to hydrolysis, while retaining desirable steric and electronic characteristics.(1−3) These features have been employed in the design of inhibitors of dipeptidyl peptidase IV (DPP4), thermolysin, and the HCV NS5A replication complex cofactor.(167,168) In peptidomimetic design, fluoroalkenes have been explored as peptide-bond surrogates to amplify or attenuate chemical properties and obtain a deeper understanding of the structure and function of a peptide or protein. For example, the influence of the prolylamide bond geometry on the inhibition of DPP4 has been investigated.(169)

Figure 8

Figure 8. Fluorinated alkenes can serve as isosteres of a ketone, ester, or amide (A) or a carbonyl moiety (B), depending on the specific structural arrangement.

While fluorinated alkenes have been explored broadly in medicinal chemistry, limited information is available on their metabolic pathways. However, fluorinated alkene moieties are found in HFCs and perfluorocarbons, and studies of these compounds have provided some insight into their metabolic fate. HFCs consisting of only carbon, fluorine, and hydrogen atoms were designed as refrigerants with lower greenhouse-gas potency relative to ozone-depleting refrigerants such as 1,1,1,2-tetrafluoroethane (153) and CFCs such as trichlorofluoromethane (154).(104) Among the marketed fluorinated refrigerants are 2,3,3,3-tetrafluoropropene (155) and 1,3,3,3-tetrafluoropropene (156). The environmental advantage of 155 stems from its short atmospheric lifetime of approximately 11 days, which is a significant improvement over that of 153 (14.6 years), and its decomposition to trifluoroacetic acid (67), which is subject to wet and dry deposition.(170,171) On the other hand, perfluorocarbons have been used to produce fluorinated carbon chain polymers that are components of household and commercial products such as waterproofing agents, lubricants, and sealants.
Fluorinated alkenes caused varying degrees of acute toxicity in rats following 4 h of inhalation, with LD50 values ranging from 40 000 ppm for 157 and 3000 ppm for 158 to <1 ppm for 159.(172) The observed toxicity coincided with the inherent electrophilicity of these molecules, with the lesser-substituted termini of 158 and 159 predisposing toward nucleophilic substitution at these sites.(172) The addition of a nucleophile to 157159 gave rise to carbanionic intermediates that eliminated fluoride to restore an olefin moiety (Scheme 22). The reactivity of the double bonds of 157159 increased in a fashion commensurate with the stability of the proposed carbanion intermediates (159 > 158 > 157), as captured in Figure 9.(172−174) In the case of 158 and 159, elimination of fluoride from the intermediate carbanion (163) afforded conjugates where the biological nucleophile became substituted with an allyl moiety (165; Scheme 22, path b, purple) rather than a vinyl moiety (164; Scheme 22, path a, red). Therefore, the rank order of the acute toxicities (LD50 values) of these perfluorinated olefins in rats suggested a chemical reaction with biological macromolecules as a key step underlying the adverse effects.

Scheme 22

Scheme 22. Proposed Nucleophilic Substitution of 1,1,3,3,3-Pentafluoro-2-(trifluoromethyl)prop-1-ene (158) with Nucleophiles

Figure 9

Figure 9. Correlation among the reactivity of perfluorinated olefins, the stability of carbanion intermediates, and lethality.

The intrinsic chemical reactivity of perfluorinated alkenes toward nucleophiles may explain the lethality observed in acute inhalation studies. However, long-term toxicology studies of fluorinated olefins that are characterized by low acute toxicity have revealed that the differentiated effects on tissues and cellular compartments (e.g., genotoxicity, cytotoxicity, hepatotoxicity, nephrotoxicity) can be attributed to other metabolic pathways. Among the fluorinated alkenes, vinyl fluoride (160) is notable because of its use as a monomer in the production of polyvinyl fluoride and other fluoropolymers.(175) The primary safety concern with 160 is occupational exposure via inhalation that exceeds the maximum levels recommended over intervals of 8 h (1 ppm) or 15 min (5 ppm).(176,177) In cancer bioassays, inhalation of 160 produced exposure-dependent hepatic, pulmonary, and Harderian gland tumors in rats and hepatic and Zymbal gland tumors in mice.(176) The spectrum of carcinogenic effects associated with 160 in laboratory animals was similar to those of vinyl chloride (161) and vinyl bromide (162), a known and a probable human carcinogen, respectively, implicating 160 as a probable human carcinogen.(177−179) Multiple observations from mutagenicity and clastogenicity studies have been used to establish the mechanisms underlying carcinogenicity induced by 160.(176) Exposure to 160 was associated with dose-dependent mutagenicity in Salmonella typhimurium (strain TA1535) and caused hprt forward mutations and chromosomal aberrations in Chinese hamster ovary cells in the presence of Aroclor-1254-induced rat liver S9.(176) However, the results of cytogenetic assays in rats were equivocal, with no DNA strand breaks or cross-links found.(176)
Since 160 was mutagenic upon metabolic activation in susceptible bacteria, a mechanism was proposed that involved the formation of chemical intermediates that would react with genetic material. The postulated mechanism, which was informed by the known chemical toxicology of 161 and 162, involved oxidation of 160 to fluoroethylene oxide (166) followed by conversion to fluoroacetaldehyde (6) and fluoroacetic acid (5) (Scheme 23).(180,181) The enzyme responsible for the initial epoxidation was CYP2E1, which is expressed in the target tissues (e.g., liver, lung) of nonclinical species and is known to prefer small xenobiotics as substrates. Inhibition (by 4-methylpyrazole) and induction (by EtOH) either blocked or enhanced the metabolism of 160, respectively, in agreement with this hypothesis.(182) In addition, the hepatotoxicity of 160 in rats was exacerbated upon coadministration of trichloropropylene oxide, an inactivator of epoxide hydrolase that would interfere with detoxification of 166 by hydrolysis, further supporting the importance of this fluorinated epoxide in the onset of toxicity.(183)

Scheme 23

Scheme 23. Metabolic Activation of 160 by CYP2E1 to Generate Fluoroethylene Oxide (166), a Reactive Intermediate That Can Modify DNA Bases or Form Downstream Products
Epoxide 166 is characterized by inherent ring strain, while its intrinsic electrophilicity is enhanced by the electron-withdrawing fluorine substituent. This set of circumstances facilitated the reaction of 166 with nucleophilic nitrogen atoms of DNA bases, a reaction that led to the formation of 7-(2-oxoethyl)guanine (173), a product of DNA alkylation that was observed in rats following exposure to the related olefin 161 (Scheme 23).(180,184) Another outcome involved adduction of the primary amine moiety leading to 169, which degraded to 170 and then cyclized to 171. Dehydration of 171 produced N2,3-ethenoguanine (172), which can cause miscoding mutations characterized by GC to AT transitions.(185,186) Rodents exposed to 160 (up to 2500 ppm for 12 months) exhibited levels of hepatic 172 that correlated positively with tumor incidence (hemeangiosarcoma), further demonstrating the quantitative relationship between modification of genetic material by 160 intermediates and genotoxic outcome.(187,188) Although 6 could theoretically react with the nucleic acids to form adducts, studies of 160 have implicated the epoxide intermediate 166 in DNA alkylation leading to mutagenic effects.(186)
In addition to genotoxicity, studies in rats indicated that administration of 160 increased acetyl-CoA levels and exhalation of acetone, suggesting incorporation of 5 into the citric acid cycle and disruption of energy metabolism.(189) Moreover, incubation of 160 in RLM resulted in N-alkylation of the porphyrin ring of P450 enzymes, rendering them inactive.(190) The modification of the heme moiety was likely initiated by a free radical intermediate derived from 160.
Whereas 160 was mutagenic following metabolic activation by P450, its perfluorinated analogue 157 caused renal toxicity, but not hepatotoxicity, via a distinct metabolic route.(191,192) Since 157 is a key monomer for the production of polytetrafluoroethylene (Teflon) and other polymers, its toxicity in laboratory animals is well-documented.(193) The nephrotoxicity of 157 manifested as dose-dependent renal tubule karyomegaly, which was evident in mice exposed to 157 at more than 1250 ppm over 15 and 90 days.(194) Metabolic activation of 157 was independent of P450, as suggested by the finding that inhibition of the monooxygenases by CO did not affect its metabolism.(191) Instead, the double bond of 157 was subject to direct GSH conjugation by hepatic microsomal GST in rats.(191) Although the primary addition product S-(1,1,2,2-tetrafluoroethyl)GSH (174) was absent from bile, its downstream products, specifically S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (175) and a minor cysteinylglycine conjugate, were detected, suggesting rapid processing of 174 by γ-glutamyl transpeptidase and dipeptidase in bile canaliculi or hepatocytes (Scheme 24). It is believed that 175 is reabsorbed and further metabolized by renal β-lyase to generate a reactive and cytotoxic product, 1,1,2,2-tetrafluoroethane-1-thiolate (176) along with pyruvic acid and NH3. Direct evidence linking 175 to nephrotoxicity was obtained in experiments that recapitulated the adverse renal effects of 157, including renal cell proliferation and histopathological changes in the tubules, following oral administration of synthetic 175 to rodents for 12 days.(191,192) The role of renal uptake of 175 in the expression of nephrotoxicity was further confirmed by the observation that coadministration of 175 with the renal anion transporter inhibitor probenecid blocked the toxicity in rats. While the ultimate toxicant in this example remains unknown, it is postulated that 176 may suffer loss of fluorine to give 177, an electrophilic thionoacyl fluoride derivative capable of thioacylating cellular macromolecules.(195) Similar findings have been reported during the study of other nephrotoxic haloalkenes, including chlorotrifluoroethylene (178), 1,1-dichloro-2,2-difluoroethylene (179), 1,1-dibromo-2,2-difluoroethylene (180), and hexachlorobutadiene (181).(196−199) Additional mechanistic studies have suggested that the nephrotoxicity of 175 may be exacerbated by an additional effect on ion transport.(191)

Scheme 24

Scheme 24. Proposed Metabolic Pathway of 157 Leading to Tissue-Selective Toxicitya

aThe reaction of 157 with hepatic GSH generates S-(1,1,2,2-tetrafluoroethyl)GS (174), which is processed to S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (175) and excreted into bile. Following absorption, 175 undergoes β-lysis to form the thiolate intermediate 176 along with pyruvic acid and ammonia. Elimination of fluoride from 176 generates the reactive thionoacyl fluoride 177, which is hypothesized to be the ultimate toxicant.

The first several steps of the GSH-dependent metabolic modification of 2-bromo-2-chloro-1,1-difluoroethylene (182), a decomposition product of halothane (94), mirrored those of 1,1-difluoroalkenes (Scheme 25). This compound was metabolized to the cysteine conjugate 183, which was converted by β-lyase to the ethanethiolate 184, a molecule that eliminated F to give 185. It was postulated that 185 underwent a series of reactions that involved dehalogenation, hydrolysis, and loss of H2S to form glyoxylic acid (191), the ultimate product of the metabolism of 182 in rat kidney homogenates and in vivo.(195,196)

Scheme 25

Scheme 25. Metabolism of 2-Bromo-2-chloro-1,1-difluoroethylene (182)

3.2. Fluorinated Alkenes as Mechanism-Based Enzyme Inhibitors

In addition to their uses as refrigerants and polymer precursors, fluorinated alkenes (monofluoro or gem-difluoro derivatives) have been employed in the design of MBIs of several enzymes.(200) These irreversible inhibitors, although chemically inert in solution, typically mimic the native substrate of the target enzyme and undergo metabolic activation to an electrophile that reacts with the enzyme or its cofactor. To inactivate a target enzyme selectively, these electrophiles must react prior to diffusing from the active site. Consequently, the intrinsic chemical reactivity of the electrophile is a key consideration in their design. Fluorine has proven useful as a leaving group in this context, with its diminutive size minimizing steric interference and facilitating substrate mimicry and recognition by enzymes.(200) These features represent advantages of fluorine relative to other halogen substituents. This section describes the design and postulated mechanisms of fluorinated alkenes as irreversible inhibitors of enzymes that are involved in a variety of biochemical processes.
Squalene monooxygenase (SM), sometimes called squalene epoxidase, catalyzes the conversion of squalene (192) to (3S)-2,3-oxidosqualene (193), the first and rate-limiting step in the biosynthesis of sterols in mammals, plants, and fungi.(201,202) This enzyme uses molecular oxygen to effect the epoxidation and requires NADPH and FAD as cofactors (Scheme 26).(203) Hence, SM is a potential therapeutic target in the design of drugs to treat fungal infections, hypercholesterolemia, and cancer.(201,202) While reversible SM inhibitors have been described, replacement of the terminal methyl groups of squalene by fluorine atoms afforded the time-dependent SM inhibitors 194 and 195.(204) Both the orientation of the difluorinated olefin and the chain length were suggested to be important for inhibition, since the sterically more congested analogues 196 and 197, which incorporate branched or elongated fluorinated olefins, did not inactivate SM. Dithiotheritol (500 μM) did not prevent inhibition by 194 or 195 in vitro, suggesting that these compounds inactivated SM without reentering solution. Although the mechanism of inhibition of these compounds was not articulated, it is reasonable to believe that 194 and 195 undergo oxidation by SM to form fluorinated epoxides that are more electrophilic than 193. Interestingly, the monofluoro derivatives 198 and 199 and the non-fluorinated compound 200 were weaker inhibitors of SM, highlighting the influence of the fluorine atoms on the potency and epoxide electrophilicity.(204)

Scheme 26

Scheme 26. Conversion of Squalene (192) to (3S)-2,3-Oxidosqualene (193) by Squalene Monooxygenase, the Initial Step in the Biosynthesis of Sterols
S-Adenosyl-l-homocysteine hydrolase (SAHase) is an NAD+-dependent enzyme that regulates transmethylation reactions in many organisms and helps maintain cellular function.(205,206) Inhibition of SAHase leads to a build-up of S-adenosyl-l-homocysteine, turning off intracellular transmethylation via a feedback loop. The broad-spectrum antiviral agent neplanocin A (201), an analogue of cyclopentenyl adenosine, is a reversible type-I MBI of SAHase (Ki = 8.39 nM) that is converted by the enzyme to the 3′-keto product 203, forcing the unproductive consumption of NAD+ (Scheme 27).(207,208) An effort to improve the potency of this compound led to the discovery of fluoroneplanocin A (202), a compound characterized by a degree of irreversible enzyme inhibition that was, surprisingly, nonstoichiometric.(209) Further analysis revealed 202 to exhibit a mixed mode of inhibition that was characterized by both reversible type-I and irreversible type-II behavior.(209) The 3′-keto variants of both inhibitors, 203 and 204, exited the enzyme, resulting in type-I reversible inhibition, and both underwent nucleophilic attack by SAHase, forming 205 and 206, respectively. However, only 206 eliminated fluoride to bind irreversibly (207; Scheme 27). This mixed mode of inhibition contributed to the improved potency observed in the case of the fluorinated homologue 202.(209)

Scheme 27

Scheme 27. Proposed Mechanisms of Inhibition of SAHase by Neoplanocin A (201) and Fluoroneplanocin A (202)
The flavin-dependent monoamine oxidases MAO-A and MAO-B catalyze the oxidative deamination of aminergic neurotransmitters and dietary amines.(210−212) Although inhibition of MAOs was explored as a means of therapeutically elevating levels of neurotransmitters in the brain, the pharmacology was complex since these isoforms are differentially expressed in tissues and differentially engaged by substrates and inhibitors. MAO-A exhibits broader substrate specificity, metabolizing both neurotransmitters (e.g., norepinephrine, serotonin, and dopamine) and dietary amines (tyramine), whereas MAO-B is mainly involved in the metabolism of dopamine and arylalkylamines.
Following the introduction of nonselective MAO inhibitors to treat depression in the 1950s, their safety was compromised by a phenomenon known commonly as the cheese effect. Inhibition of MAO-A by these medicines led to a spike in the levels of tyramine, a naturally occurring compound abundant in certain foods such as cheese, to dangerous levels that were associated with cardiovascular events and hypertension. While l-deprenyl (selegiline, 208), a selective and irreversible inhibitor of MAO-B used for the treatment of early-stage Parkinson’s disease, did not cause such effects at therapeutic concentrations, its plasma levels became elevated by interaction with oral contraceptives to the extent that the adverse effects related to inactivation of MAO-A were evident.(213)
Fluorinated inhibitors of MAO with improved isoform selectivity were investigated in clinical trials in the 1980s. As a representative of the fluorophenyl allylamine class, mofegiline (209) was developed as an irreversible inhibitor of MAO-B that exhibited good potency and 200-fold selectivity over MAO-A.(214,215) The p-fluorophenyl substituent contributed to the superior isoform selectivity over MAO-A, of which 209 was a weak and reversible inhibitor. The mechanism of inhibition of MAO-B by 209 involved oxidation of the primary amine to yield an iminium-based Michael acceptor 210 that was subject to nucleophilic attack at the terminus of the fluorinated olefin by the cofactor to afford 211, as depicted in Scheme 28. The departure of fluoride from 211 resulted in irreversible binding to the cofactor and inactivation of the enzyme (212).(214,215)

Scheme 28

Scheme 28. Inhibition of MAO B by Mofegiline (209)a

aThe inhibition results from oxidation of the primary amine to the conjugated iminium 210, a Michael acceptor that reacts with N5 of the flavin coenzyme, forming the covalent adduct 211. Loss of fluoride from 211 results in the formation of a covalent complex (212).

Mofegiline (209) also exhibited off-target effects via the inhibition of semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1), an enzyme that oxidizes primary amines to aldehydes, releasing NH3 and H2O2 in the process.(216,217) Inactivation of SSAO/VAP-1 led to an anti-inflammatory effect in preclinical species.(218) The primary amine of 209 was believed to act as a nucleophile in its interaction with SSAO/VAP-1, condensing with the cofactor 2,4,5-trihydroxyphenylalanine (213) in its quinone form 214 (topaquinone) to give the quinone imine 215 (Scheme 29). Tautomerization of 215 afforded the electrophilic conjugated imine intermediate 216. This imine reacted with the enzyme to afford 217, a compound that released fluoride to give the irreversibly bound conjugate 218. The characterization of this pathway led to the discovery of additional irreversible inhibitors of SSAO/VAP-1 that retained the fluorinated olefin and primary amine moieties but were devoid of activity against MAO B.(219)

Scheme 29

Scheme 29. Inactivation of SSAO/VAP-1 by Mofegiline (209)a

aMofegiline is believed to condense with (2,4,5-trihydroxyphenyl)alanine quinone (214), the SSAO/VAP-1 cofactor, to form the quinone imine 215. Tautomerization of 215 affords the conjugated imine 216, which is intercepted by a proximal nucleophilic amino acid residue to give 217. This intermediate can eliminate fluoride, leading to the irreversibly inactivated enzyme 218.

The pharmacokinetics and disposition of 209 were investigated in both preclinical species and humans.(220) Urine samples that were collected following oral administration of 209 contained four major metabolites, 219, 220, 222, and 223, which collectively accounted for 70% and 40% of the dose in dogs (collection interval of 0 to 24 h) and humans (0 to 8 h), respectively (Scheme 30). The initial step in the formation of both 222 and 223 was believed to be the addition of CO2 to the primary amine moiety of 209 to form the carbamic acid intermediate 221 (Scheme 30). As depicted in Scheme 31, oxidation of the fluorovinyl moiety of 221 afforded the epoxide 224, which was subject to an intramolecular nucleophilic attack by the pendent carboxylate to afford aldehyde 225 via an unstable fluorohydrin intermediate that released fluoride. Subsequent oxidation of 225, presumably by aldehyde oxidase, gave rise to the carboxylic acid 222.(220)

Scheme 30

Scheme 30. Metabolic Pathways of Mofegiline (209) in Dogs and Humans

Scheme 31

Scheme 31. Proposed Mechanism for the Formation of 222 from 209 via Carbamic Acid 221
Glucuronidation of the carbamic acid 221 by UGT provided 223, while succinylation of the primary amine function by N-succinyl transferase gave 219. The urea derivative 220, an unusual enamino aldehyde, was proposed to form via the multistep reaction depicted in Scheme 32. Completing the metabolite profile, oxidative deamination of 209 by MAO afforded the fluorinated α,β-unsaturated aldehyde 226, which reacted with H2O to give an unstable fluorohydrin intermediate. This intermediate released fluoride to give the dialdehyde derivative 227, which was subject to condensation with urea to generate the final product 220.(220)

Scheme 32

Scheme 32. Proposed Mechanism for the Formation of 220 from 209
Although fluorinated alkenes have been exploited in the design of covalent inhibitors, they can also react with enzymes in ways that might be difficult to anticipate. CPP-115 (228) represents an example of a fluorinated alkene that was designed as an MBI of γ-aminobutyric acid aminotransferase (GABAAT) but engaged the enzyme in an unexpected manner.(221) By way of background, GABAAT is a PLP-dependent enzyme responsible for degrading the inhibitory neurotransmitter γ-aminobutyric acid (GABA).(222) Inhibition of GABAAT leads to elevated levels of GABA in the brain and can help patients overcome seizures or substance abuse. MBIs of GABAAT have been designed that resemble the natural substrate in their interactions with PLP, with the introduction of structural modifications designed to effect covalent binding to the enzyme and interrupt enzymatic function.(222) Vigabatrin (229, γ-vinyl-GABA or 4-amino-5-hexenoic acid) remains the only such GABAAT inhibitor approved to treat infantile spasms and refractory partial seizures.(223) However, 229, which is administered at doses of 500 mg or more twice daily, has been associated with severe clinical adverse effects, including nephrotoxicity and blindness. The proposed mechanism for the reaction between GABAAT and 229 is illustrated in Scheme 33. This mechanism postulated two possible outcomes from the intermediate 230, with the major path (path a, 70%) irreversible and the minor path (path b, 30%) reversible. Path a proposed that 230 was deprotonated by the catalytic Lys329 to afford an α,β-unsaturated iminium that reacted with Lys329 to produce 231, a complex that was stable toward denaturing conditions and was characterized by X-ray crystallography.(224) Path b postulated that the olefin moiety participated in deprotonation of 230 to produce an aminal-type intermediate that degraded with release of the nucleophilic enamine 232. This enamine was poised to react with the GABAAT-Lys iminium species to give 233.

Scheme 33

Scheme 33. Proposed Mechanism of Irreversible (Path a) and Reversible (Path b) Inhibition of GABAAT by the GABA Mimic Vigabatrin (229)
To improve on the properties of 229, the conformationally restricted and fluorinated analogue 228 was prepared. This compound was designed to give rise to an intermediate that would be a more reactive Michael acceptor and, by extension, a more efficient inactivator of GABAAT than 228.(225) Indeed, 228 was 187-fold more potent than 229 and offered a clinical profile that suggested favorable absorption, distribution, metabolism, excretion, and safety properties.(226) However, a study of the inhibitory mechanism associated with 228 revealed some unexpected findings, including the absence of any covalent modifications to GABAAT, as evidenced by intact mass spectrometry of the protein following treatment with 228. An X-ray crystal structure of this protein revealed the orientation of the ultimate inhibitor and demonstrated that 228, although designed to inhibit GABAAT irreversibly via a Michael addition, actually engaged in a multistep defluorination pathway to yield the dicarboxylic acid 240. This acid formed tight electrostatic interactions with the two key arginine residues Arg192 and Arg445 of the enzyme and induced a conformational change in the active site (Scheme 34).(226) It was postulated that the addition of H2O to 236, rather than the catalytic Lys329 as observed with 229, was preferred since the electrophilic center was not presented in a geometrical orientation that was compatible with a productive reaction with Lys329. While 228 was reported to exhibit good stability in human hepatocytes (half-life = 20 h) and short half-lives in preclinical pharmacokinetics studies (1 to 2.3 h in the rat and dog), metabolite profiles of the compound from these studies have not been published.(226)

Scheme 34

Scheme 34. Proposed Mechanism of Irreversible Inhibition of GABAAT by 228a

aThe inhibition is initiated by formation of the Schiff base 234 with PLP (a). Arg192 engages the carboxylate moiety to anchor the inhibitor in the active site of the enzyme. Tautomerization (b) of 234 generates the Michael acceptor 236, which is subject to successive hydrolytic reactions (c and d) that liberate 2 equiv of fluoride to ultimately produce 238. Because of conformational restrictions, 236 reacts with H2O rather than the catalytic Lys329 to form an unstable difluorohydrin, which degrades to the acyl fluoride 237 and then to PLP-bound diacid 238. The nascent carboxylate in 238 is positioned to engage in a second electrostatic interaction with Arg445. Hydrolysis of 238 (e) releases PLP-derived amine 239 and (1S)-4-oxocyclopentane-1,3-dicarboxylate (240), which can spontaneously undergo decarboxylation (f) to give (S)-3-oxocyclopentane-1-carboxylate (241).

4. Fluorinated Ethers

ARTICLE SECTIONS
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4.1. Fluorinated Alkoxy Substituents

During compound optimization, the substitution of alkoxy groups with fluorinated homologues (e.g., OCH3 to OCF3 or OCHF2) is an approach that has been used to modify both physicochemical properties and metabolite profile.(227,228) As substituents, OCF3 groups usually confer enhanced lipophilicity compared with OCH3. This effect reflects both the higher intrinsic lipophilicity of fluorine (π = 0.14) and the inductive electron-withdrawing effects of fluorine that reduce the hydrogen-bond-accepting (pKHBX) character of the oxygen atom.(227−230) However, exceptions to this trend have been noted, many of which involve a close proximal relationship between a fluorine substituent and an oxygen-containing functionality that is believed to impart increased overall polarity to a molecule, thereby favoring solvation in polar media.(4) Increased lipophilicity is evident in higher measured log D values, but counterintuitively, this substitution may actually detract from passive permeability. Such a trend was noticed during an analysis of matched molecular pairs containing anisole (PhOCH3) and trifluoroanisole (PhOCF3) in the corporate compound collection at Pfizer.(231) The substitution of anisoles with trifluoroalkoxy groups alters the conformational preference of the substituent from coplanar to orthogonal with respect to the aromatic system. This arrangement relieves conformational strain by reducing orbital overlap between the oxygen electron lone pair and the aryl ring. The orthogonal OCF3 substituent is larger and is believed to be more susceptible to steric forces exerted by constituents of the cell membrane that slow its passage across the monolayer, resulting in impaired membrane permeability.
Perhaps the most common reason to explore substitution with OCF3 in place of OCH3 or CH2CH3 is to avert a biotransformation pathway involving O-demethylation and/or to decrease the overall rate of oxidative metabolism.(231−233) This approach is intuitive since the rate-limiting step in an O-demethylation reaction is the abstraction of a hydrogen atom from the CH3O group, a process than cannot occur when the H is replaced by F. However, the success of this approach has been mixed.(228) While reports of reduced metabolic clearance and extended pharmacokinetics of compounds containing OCF3 continue to be described,(229,234) the Pfizer survey found no consistent improvement in metabolic stability for trifluoroanisoles compared to anisoles.(231) Considering the breadth of the data set, the reasons for this lack of a trend are likely varied. In some cases, the OCH3 moiety does not represent the main metabolic soft spot, while in others, the additional lipophilicity conferred by OCF3 may impart stronger affinity for drug-metabolizing enzymes like P450. A third possibility is that metabolizing enzymes may be able to catalyze O-demethylation via an alternative mechanistic route that does not involve the direct cleavage of a C–F bond. Such an explanation was invoked when OSI-930 (242), a c-Kit/VEGFR inhibitor that was advanced into clinical development for the treatment of cancer, was observed ostensibly to undergo O-detrifluoromethylation in a preclinical study using rats and again in a separate experiment using liver microsomes.(235) An ipso substitution pathway that involved the loss of the OCF3 moiety as a leaving group was proposed to explain the observation (Scheme 35). Certain features of this mechanism, including the formation of the hemiketal intermediate 244 and the overall displacement of an alkoxy group by hydroxyl, found precedent in classic work on the bioactivation of phenacetin and acetaminophen that had been performed in the 1970s.(236) In those studies, multiple pathways for the O-deethylation of phenacetin had been described, one of which proceeded with quantitative incorporation of atmospheric 18O at the site of substitution. Hence, it is well-established that metabolic processes that appear to involve O-dealkylation of aromatic ethers may actually proceed by a displacement reaction that involves either ipso substitution or epoxide formation. The extension of this concept to include the displacement of OCF3 groups has been readily accepted since halogens, which are characterized by similar degrees of electronegativity relative to OCF3, are also subject to displacement from aryl rings during metabolism.(237) In the case of OCF3 substituents, the reaction would liberate fluorophosgene (246) as a byproduct of O-dealkylation. Since 246 exists as a gas at standard temperature and pressure, studies of its toxicology have only explored inhalation as the route of administration. For this reason, it is difficult to connect the dose of 246 that might be liberated during the metabolism of a difluoromethoxy-substituted compound to the toxicological effects of direct exposure. However, it is sensible in the interest of safety to take steps to limit the formation of 246 as a metabolite, as its toxicity is known to be severe.(238)

Scheme 35

Scheme 35. Proposed Mechanism of the Metabolism of OSI-930 (242)a

aOSI-930 (242) undergoes single-electron oxidation by P450, creating a radical intermediate that exists in both nitrogen- and carbon-centered resonance forms (243) prior to recombination/rebound hydroxylation. The resulting hemiketal 244 loses CF3OH, which rapidly degrades to fluorophosgene (246) at room temperature, producing the transient quinone imine intermediate 245. Quinone 245 is then reduced to the observed hydroxyphenyl metabolite 247.

The deployment of difluoromethoxy (OCHF2) substituents is intended to strike a balance between the properties of OCH3 and OCF3. The OCHF2 motif has been suggested to offer consistent improvements in several metrics, including lower log D and increased passive cellular permeability relative to OCF3 and slightly lower rates of oxidative metabolism compared with OCH3.(231) Examples of clinically evaluated compounds incorporating metabolically stable OCHF2 substituents are the β-secretase inhibitor 248; the antifibrotic agent FT061 (250), an analogue of the antiallergic drug tranilast (249) that was effective in a rodent model of diabetic nephropathy; and AZD0837 (251), the prodrug of a direct inhibitor of thrombin that was evaluated clinically as a treatment for venous thromboembolism.(239−242) Additional examples include pantoprazole (252), an irreversible proton-pump inhibitor marketed for the treatment of gastroesophageal reflux disease (GERD), CHF 6001 (253), an inhibitor of phosphodiesterase-4 (PDE-4) that was of interest as a potential treatment for pulmonary inflammation, and the long acting PDE-4 inhibitor roflumilast (254) that is approved to treat chronic obstructive pulmonary disease.(243−245) Roflumilast is metabolized to the pyridine N-oxide, an equally active metabolite that is believed to account for 90% of the PDE-4 inhibitory activity of the drug in vivo. The increased electronegativity associated with the OCHF2 substituent of 248 resulted in a reduction in P-glycoprotein-mediated efflux across the blood–brain barrier, enhancing brain penetration for this centrally acting compound.(240) Metabolic stability was also improved relative to compounds with unsubstituted methoxy substituents, presumably because those groups represented soft spots for oxidative metabolism. Furthermore, short-chain alkoxy substituents resulted in improved metabolic stability in liver microsomes relative to longer-chain groups, although the relationship was also influenced by aromatic fluorine substitution at distal sites within the series. This finding reaffirms the point that such trends between structure and metabolic stability are highly context-dependent and may be influenced by remote interactions in a way that can be difficult to anticipate.
The use of OCHF2 moieties to avert O-demethylation has been described in other studies. For example, this structural element is featured in several PDE4 inhibitors that have been explored for their anti-inflammatory effects against aberrant immune cells.(246−249) However, several of these compounds were eventually recognized to carry on-target liabilities that were exacerbated in some cases by high exposure.(245) In light of these issues, intratracheal/intranasal administration of CHF 6001 (253) was explored as a treatment for inflammatory pulmonary disorders, and despite extensive metabolism of the compound in rats prior to disposition, the difluoromethoxy group of [14C]-253 remained intact in all metabolites identified in the urine and feces.(244) Similarly, metabolite profiling studies of AZD0837 (251) and pantoprazole (252) in vivo were completed without any report of biotransformation of the OCHF2 moieties of these compounds.(242,243) Substitution with OCHF2 was explored further during an effort to produce analogues of the antifibrotic agent tranilast (249) with improved pharmaceutical properties.(241) While this initiative was able to produce a candidate (250) with lower clearance in vivo and no associated increase in the volume of distribution, the improvement in pharmacokinetics was ascribed to an increase in the extent of protein binding that helped to sequester the compound from drug-metabolizing enzymes.
Despite these endorsements, the collective experience with OCHF2 groups as a replacement for either OCF3 or OCH3 has not found them to be uniformly inert. Biotransformation studies of BMS-665053 (255), a corticotropin-releasing factor (CRF) receptor-1 antagonist that was investigated as a potential treatment for depression and anxiety, revealed an apparent example of O-dedifluoromethylation as part of a metabolic pathway leading to downstream GSH and glucuronide conjugates in rats.(250) It remains unclear whether the intermediate formed along the bioactivation pathway leading to the GSH conjugate was the epoxide 256 (Scheme 36, path a), which reacted with GSH and expelled formyl fluoride (258)(251) to generate 259, or the quinone imine 261 (Scheme 36, path b), which was formed by direct O-dealkylation by P450 to afford 260 as the precursor. However, the observation of the glucuronide conjugate 262 but not phenol precursor 260 suggested that the latter pathway was at least operative, if not fully responsible for the formation of both metabolites.(250) While the identification of ways to avert bioactivation in this series of CRF receptor antagonists became a focus of the optimization campaign and the evaluation of additional compounds brought the relationship between structure and bioactivation into better focus, the analogues with the best composite profile retained the OCHF2 moiety. However, none of these analogues was able to avoid the formation of reactive metabolites entirely.

Scheme 36

Scheme 36. Proposed Metabolic Pathways to Explain the Formation of Metabolites Observed with the CRF Receptor Antagonist BMS-665053 (255)
The direct displacement of OCHF2 groups by biological thiols has also been demonstrated in the context of the pyrido[2,3-b]pyrazine 263, which was observed to undergo nucleophilic displacement of the 3-substituent by GSH in rat liver S9, a matrix where GSTs are plentiful.(252) Interestingly, the same compound also reacted spontaneously in buffer (pH 7.4, 37 °C) with either of the two peptides Ac-FAACAA or Ac-YACAKASAHA. Positive-ion electrospray MS/MS was used concurrently to show that the OCHF2 group had been displaced by the cysteine residues of these peptides, indicating that the reaction was common among biological thiols and could proceed in the absence of catalytic enzymes (Scheme 37). Thus, while the OCHF2 moiety can confer metabolic stability relative to OCH3 and OCF3 in many circumstances, it can still serve as a leaving group if deployed in the context of heterocycles that are inherently susceptible to nucleophilic displacement reactions.

Scheme 37

Scheme 37. Displacement of the OCHF2 Group in 263 by a Biological Thiol
In contrast to the popularity of the OCHF2 group in drug design, the OCH2F moiety is deployed rarely, and a full understanding of its metabolic pathways is lacking. Perhaps the best known example of a compound exhibiting this functionality is the anesthetic agent sevoflurane (98), which occasionally causes hepatotoxicity.(22) It should be noted that the metabolism of 98 is the result of a complex, multistep pathway (Scheme 18) that results in the eventual cleavage of the OCH2F moiety in the final step of the sequence.(141) Although a few plausible mechanisms have been suggested to explain how this step occurs, evidence to distinguish among them has not been published. Thus, it remains unclear whether the observed loss of OCH2F from 98 has any implications for the metabolism of other compounds incorporating this structural element.
Another motif with low representation in the medicinal chemistry literature is the α,α-difluoroethoxy (OCF2CH3) moiety, which offers interesting properties compared with the OCF3 and CH2CH3 substituents.(227,253) Chromatographic measurements of log P values indicate that the α,α-difluoroethoxy moiety in 270 confers higher polarity than either the OCF3 (268) or CH2CH3 (269) analogue.(254)However, the OCF2CH3 moiety was recently shown to be hydrolytically sensitive as a function of its chemical environment. Specifically, metabolism of 1-(1,1-difluoroethoxy)-4-methoxybenzene (271) by C. elegans resulted in the unexpected formation of 4-acetoxyphenol (275) instead of the anticipated 4-(1,1-difluoroethoxy)phenol (272).(253) This observation was explained by chemical degradation of the primary phenol metabolite 272 facilitated by improved stability of the oxonium ion 273 compared with the methoxy progenitor 271 (Scheme 38). Notably, α,α-difluoroethyl sulfides, close analogues bearing a sulfur atom in place of oxygen in this series, were not found to be similarly unstable, and metabolism of the sulfur analogue of 271 proceeded via S-oxidation and O-demethylation to afford chemically stable products.

Scheme 38

Scheme 38. Metabolism of 271 by C. elegans, Which Catalyzes O-Demethylation of the Anisole Methyl Moiety to Afford the Hydrolytically Sensitive Product 272
In the two examples reported to date, the 2,2,2-trifluoroethoxy (CF3CH2O) moiety was resistant to metabolism. This finding was based on a comparison of the rates of metabolism of 7-ethoxycoumarin (276) and phenacetin (278), both of which are known substrates of P450 deethylase activity, with those of the 2,2,2-trifluoroethyl analogues 277 and 279.(150) In phenobarbital-induced RLM, the degradation rates were 1.93 and 3.48 nmol min–1 (mg of protein)−1 for 276 and 278, respectively, whereas the rates of metabolism of 277 and 279 were too low to quantify. Additional studies ruled out the possibility that the difference could be ascribed to P450 inhibition by the 2,2,2-trifluoroethoxyl variants. While the origin of the enhanced stability was not explained, the inductive effect of the fluorine substituents is presumably responsible, effectively raising the energy level of the radical intermediate that is produced by H atom abstraction and decreasing the rate of reaction.

4.2. Fluorinated Dioxoles

Geminal difluorination of the benzodioxole moiety is an approach that has attracted attention as a means of improving the pharmaceutical and metabolic properties of drug candidates containing this structural motif, although the literature offers examples of both successful and unsuccessful applications. The 2,2-difluorobenzo[d][1,3]dioxole moiety is often introduced to block metabolism of the methylene analogue, which can inhibit P450 mechanistically by generation of a carbene intermediate that coordinates tightly to the Fe atom.(255) Fludioxonil (280), a nonsystemic fungicide used in agriculture to protect cereal, fruit, and vegetable crops, provides a representative example.(256) Although metabolized extensively following oral administration (100 mg/kg) in rats, with only 12% of the dose recovered as unchanged parent compound in excreta, the difluorodioxole moiety of 280 was intact in all of the metabolites that were identified in those matrices.(256) Similarly, the difluorodioxole moiety of the fatty acid amide hydrolase inhibitor JNJ-42165279 (281) was intact in all of the metabolites characterized preclinically during studies with liver microsomes (mouse, rat, dog, monkey, human) and hepatocytes (rat, dog, monkey, human).(257) These findings were recapitulated during metabolite profiling of plasma samples from rats, dogs, and monkeys following oral administration of the compound. The difluorodioxole moiety was introduced to enhance the metabolic stability of the camptothecin derivative 282, administered as its prodrug 283.(258) Since the difluorobenzodioxole motif tends to resist oxidative metabolism, specifically with respect to the formation of o-quinone metabolites that are prone to redox cycling and nucleophilic attack by biological nucleophiles, it was anticipated that psychedelic empathogens bearing this moiety would offer an improved balance of efficacy and safety. For example, compounds such as MDMA (ecstasy, 284) hold promise in the treatment of certain psychiatric disorders but have been suggested to carry neurotoxic hazards that involve metabolites.(259) Assertions regarding the neurotoxicity of 284 are controversial and have been contradicted by recent clinical work in which the drug was well-tolerated at therapeutic doses.(260) To be sure, such assertions were grounded initially in a high-profile report that was published in 2002 but ultimately retracted once it became clear that the animals in the study had been administered (+)-methamphetamine instead of 284.(261) Unfortunately, the difluoro variant 285 was not active in humans at doses up to 120 mg, a dose that falls near the high end of the dose range of 284 used clinically.(229) This finding serves as a reminder that substituting fluorine for hydrogen can profoundly alter the action of a drug, even as the metabolic properties might be improved.
While lumacaftor (286), a chaperone of the cystic fibrosis transmembrane conductance regulator protein, was excreted mostly intact in humans, small quantities of a catechol metabolite and a downstream sulfate metabolite, which were formed as the result of degradation of the fluorinated benzodioxole ring, were identified.(262) The mechanism of formation of these metabolites was not explained in the regulatory document supplied to the U.S. Food and Drug Administration, and the metabolic fate of 286 has not been elaborated in the published literature. Since the mechanistic route to this metabolite likely differs from that governing the conversion of unsubstituted dioxoles to catechols, in which the rate-limiting step involves abstraction of a hydrogen atom from the dioxole CH2, two alternative pathways that rely on arene oxidation are postulated in Scheme 39. Hypothetically, incorporation of a single equivalent of 18O would be anticipated if this reaction were conducted under controlled conditions using either an atmosphere of 18O2 (A) or 18O-labeled water (B), rendering the two mechanisms easily differentiable. Incidentally, 286 is also a weak competitive inhibitor of CYP2C8 (amodiaquine N-deethylase IC50 = 12 μM) and CYP2C9 (diclofenac 4′-hydroxylase IC50 = 32 μM), contrary to the notion that unsubstituted benzodioxoles inhibit P450 mechanistically via coordination of the metastable carbene intermediate to the Fe atom.(255,263) Thus, there are at least two lines of evidence in addition to chemical reasoning to suggest that an alternative mechanism governing this O,O-dedifluoromethylenation may apply.

Scheme 39

Scheme 39. Two Potential Mechanisms by Which Lumacaftor (286) May Be Metabolized to the Catechol 290a

a(A) Arene oxidation of 286 by P450 affords 287, which degrades via 288. The degradation pathway for 288 could occur by the direct departure of the phenolate with concomitant release of fluorophosgene (246) or via elimination of HF and hydrolysis of the carbonofluoridate product followed by decarboxylation. Collapse to o-quinone 289 is followed by reduction to the catechol 290, which is either excreted or sulfated. (B) Arene oxidation of 286 at an alternate site would afford epoxide intermediate 291, which could degrade hydrolytically to give 292. Rearrangement of this intermediate with loss of H2O and reduction by an overall mechanism analogous to that described above would afford catechol 290 via the o-quinone 289.

An interesting application of difluorinated ethers (ROCF2R′) has been in the design of MBIs of glycosidases, which have attracted attention as therapeutic targets on the basis of their ubiquity and broad range of functions.(200,264,265) In the example depicted in Scheme 40, 293 mimicked the native glycoside and was accepted as a substrate, with the difluoroether removed by the enzyme from the terminal sugar molecule to afford 294 followed by 295.(264) The α,α-difluoroalcohol intermediate 296 readily eliminated fluoride to afford the reactive acyl fluoride 297, which formed a covalent bond that inactivated the glycosidase as the adduct 298. However, the issue with this class of compounds that has prevented their widespread adoption as either drugs or experimental tools has been the tendency of the acyl fluoride 297 to be hydrolyzed by H2O or exit the catalytic pocket of the protein and react with other proteins as unintended collateral targets.

Scheme 40

Scheme 40. Mechanism-Based Glycosidase Inactivation by the Glycoside 293 Exhibiting a Difluorinated Ethera

aThe substituted ether of the glycoside is displaced (294), generating 295 and the difluorinated alcohol 296, which decays quickly to the acyl fluoride 297. The acyl fluoride then reacts covalently with an amino acid residue in the active site, inactivating the enzyme (298), or diffuses away from the enzyme and is either hydrolyzed or captured by an adventitious nucleophile such as a protein.

5. Fluorinated Amines

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5.1. Fluorinated Piperidines

The introduction of fluorine atoms proximal to an amine has found widespread application as a means of reducing basicity or modulating conformation. In turn, these effects can influence pharmacology or interfere with metabolism. While optimization of KSP inhibitors 3439 offered one example (vide supra), another example was provided by the fentanyl analogue NFEPP (300).(60,266)In contrast to the more basic 299, the fluorine atom installed in the piperidine ring of 300 restricted protonation to low-pH environments and thereby facilitated selective agonism of μ opioid receptors in damaged peripheral tissues. Similarly, in the phenylethanolamine N-methyltransferase inhibitor 301, the CHF2 substituent represented the optimal compromise compared with the lower and higher fluorinated homologues, conferring selectivity for the target enzyme relative to the α2 adrenoreceptor.(267)

5.2. Fluorinated Pyrrolidines

However, care should be exercised when configuring the relationship between amines and fluorine atoms since some arrangements can be cryptically predisposed toward metabolic activation.(27,268−270) An example is provided by pyrrolidine-based DPP4 inhibitors 302 and 303, in which the fluorinated pyrrolidine ring was a source of metabolic activation and covalent binding to protein in RLM.(268) Studies with tritiated compounds revealed that the protein binding was irreversible, dependent on both time and NADPH, and attenuated by the addition of GSH or N-acetylcysteine. By means of incubations conducted in the presence of the hard nucleophile semicarbazide, which captures aldehydes as the imine species, the metabolic pathway depicted in Scheme 41 was elucidated. This bioactivation process was hypothesized to begin with α-hydroxylation of the pyrrolidine ring of 302 or 303 to afford the hemiaminal 304. Ring opening of 304 to give the aldehyde 305 would set the stage for elimination of HF to produce the unsaturated aldehyde 306, a dual electrophile capable of cross-linking proteins. Interception of 306 by GSH would generate 307, which can exist in equilibrium with the hemiaminal 308.(268)

Scheme 41

Scheme 41. Metabolic Pathway Elucidated for the DPP4 Inhibitors 302 and 303 in RLM
The alternative pathway presented in Scheme 42 was also contemplated. This process relied on β-hydroxylation of the pyrrolidine ring of 302 or 303 to give the fluoroalcohol 309, which collapsed to the epoxide 310 with elimination of HF. Reaction of the epoxide with GSH would then afford a mixture of 311 and 312. However, this mechanism was ruled out on the basis of experiments in which the addition of an epoxide hydrolase inhibitor failed to reduce protein covalent binding. Studies with recombinant rat P450 enzymes indicated that metabolic activation was catalyzed primarily by CYP3A1 and CYP3A2. Consistent with this finding, covalent binding to protein was enhanced using liver microsomes from rats that had been pretreated with pregnenolone-16α-carbonitrile and dexamethasone, compounds that induce the production of these enzymes in vivo.(268)

Scheme 42

Scheme 42. Alternative Epoxide-Based Metabolic Pathway Contemplated for the DPP4 Inhibitors 302 and 303 in RLM
However, the presence of this fluorinated motif is not necessarily a predictor of metabolic activation since studies with several additional 3-fluoropyrrolidine derivatives have been completed without revealing overt susceptibility to such a process.(269−271) Interestingly, all of the examples described are 3,3-difluoro-substituted pyrrolidine derivatives, including the DPP4 inhibitors 313 and 314 and the HIV-1 non-nucleoside reverse transcriptase inhibitor 315. While the half-life of 315 in liver microsomes was short and the difluoropyrrolidine ring was subject to metabolism by a pathway that was not elucidated, there was no clear indication that reactive metabolites were formed. Geminal difluoro substitution would be expected to increase the lipophilicity, which in some cases may enhance the rate of oxidative metabolism by P450 enzymes.

5.3. Fluorinated Azepanes

The metabolic elimination of HF from a γ-difluorinated amine during metabolism studies has been shown to be a pathway involving bioactivation. Detailed profiling of the pan-Pim kinase inhibitor 316revealed potent time-dependent inhibition (TDI) of CYP3A enzymes with IC50 values of <100 nM.(272) This effect was observed using both testosterone and midazolam as substrates, compounds that bind to different sites of CYP3A, prompting concern about drug–drug interactions. Indeed, with a kinact/Ki ratio of 64, the CYP3A TDI was comparable to that of the reference agent mifepristone. Metabolite identification studies indicated that the fluorinated azepane ring of 316 was a major site of metabolism. Additional studies designed to illuminate the underlying mechanism focused on compounds with simpler substructures in place of the 2-substituted thiazole, seeking to probe aspects of the azepane ring configuration and substitution pattern while exploring the effects of lipophilicity and polarity. These studies, conducted in the context of a benzoyl substituent, established that TDI was not related to the chirality of the amine since the two enantiomers 318 and 319 were similarly problematic (Figure 10).(272) The dimethylamine homologue was free of TDI, but when this modification was installed in the fully elaborated thiazole analogous to 316, CYP3A TDI remained a problem, illustrating a limitation of using truncated substructures as probes. Notably, the simple non-fluorinated amino-substituted azepanes 321 and 322 were free of the liability, an observation that, together with the dimethylamine data, exonerated the nitroso pathway depicted in Scheme 43 (path a) as the source of CYP3A TDI. Since the more lipophilic desamino derivative 320 also demonstrated CYP3A TDI, consideration was given to path c as a possible contributor. However, results of GSH-trapping experiments were consistent with path b, in which α-hydroxylation of the exocyclic amine and loss of NH3 afforded a ketone, setting the stage for elimination of HF to produce the electrophilic α,β-unsaturated homologue. This model was supported by the observation of weak CYP3A TDI with the racemic hydroxyl analogue 323, which could undergo oxidation to give the same ketone intermediate and then follow a similar pathway of chemical activation. Further support came from evaluation of the α-methyl amines 324 and 325, which were unsusceptible to this pathway and confirmed to be free of CYP3A TDI.(272) While the α-methyl derivatives retained pan-Pim kinase inhibitory activity, these compounds were poorly active in cell-based assays. Further optimization of fluorination patterning, which is important as a modulator of membrane permeability and pharmacokinetic properties, resulted in the identification of the β-fluoro derivative GDC-0339 (317) as an early development candidate.(273)

Figure 10

Figure 10. Relationships between structure and CYP3A inhibition for a series of azepane derivatives.

Scheme 43

Scheme 43. Potential Metabolic Pathways Giving Rise to CYP3A TDI from Difluorinated Azepane Derivativesa

aProposed metabolic pathways that may result in TDI of P450 by 318: (a) Oxidation of the primary amine in two steps yields the nitroso derivative 326, which coordinates to the heme protein. (b) Oxidative deamination yields the ketone 327, which undergoes elimination to give the α,β-unsaturated carbonyl 328 and then nucleophilic attack by a biological thiol to give 329 and 330. (c) In the des-NH2 series, α-hydroxylation of the azepane ring to give 331 leads to conjugated imine 332 and then 333, which also undergoes nucleophilic attack to give 334.

5.4. Fluorinated Methylcyclopropyl Amines

Unexpected but strongly adverse effects were associated with oral administration of poly-ADP ribose glycohydrolase (PARG) inhibitors incorporating an N-(1-(fluoromethyl)cyclopropyl)sulfonamide substructure, with observations suggesting a role for gut metabolism on the basis of the absence of toxicity following iv dosing.(274) As background, 335 and 336exhibited short half-lives in vivo that precluded evaluation in animal efficacy models. Subsequent in vitro studies identified the sulfonamide substituent as the major site of metabolism, giving rise to the primary sulfonamide (RSO2NH2). Fluorination of the methyl substituent of the cyclopropylamino group was pursued as an approach to improve the metabolic stability, and in the initial survey, CHF2 and CF3 derivatives were found to be more stable in human liver microsomes (HLM). However, these compounds were 15- and 150-fold weaker enzyme inhibitors, respectively, while the monofluoromethyl analogue was equipotent and more metabolically stable relative to the unsubstituted methyl compound. The limited options for modification at this site focused interest in the monofluoro compounds, which were advanced into pharmacokinetics studies. In these studies, 337 suffered from high clearance, while 338 exhibited lower clearance but was toxic in vivo, producing ataxia, hepatotoxicity, and gastrointestinal bleeding. These issues became a common theme, with 10 of 11 monofluorinated compounds associated with toxicity, while the only outlier, 337, was cleared rapidly. All 10 toxic analogues elicited ataxia, with onset occurring approximately 5 h postdose and with no apparent correlation to plasma exposure, free drug levels, or PARG inhibitory activity. In contrast, a total of 24 non-fluorinated compounds were well-tolerated across doses ranging from 5 to 160 mg/kg. Collectively, these results implicated a common metabolite of the fluorinated derivatives as the ultimate toxicant, although the metabolic pathway was not elucidated.(274)

5.5. PLP-Dependent Metabolism of β-Fluorinated Amines

β-Fluorinated amino acids have been designed as MBIs of enzymes where metabolism of the amino acid involves condensation of the primary amine with the aldehyde of PLP to form an imine-based intermediate.(200,275) Enzymes that fall into this class include bacterial alanine racemase and mammalian and nonmammalian amino acid decarboxylases. Inhibition of these enzymes occurs by elimination of fluorine during metabolism, generating an electrophilic intermediate that reacts covalently with the protein.(276−288) As an example, the bacterial alanine racemase inhibitor fludalanine (340), the Cα-deuterated analogue of d-fluoroalanine (339), was advanced into clinical trials as a potential anti-infective agent.(277−279) The mechanism of inhibition by 339 entailed deprotonation of the PLP-based intermediate 344 followed by departure of fluoride from 345, as summarized in Scheme 44.(276−279) The loss of fluoride usurped the normal pathway of deprotonation/reprotonation that occurred with the natural substrate alanine to afford 346, an intermediate of low electrophilicity. Exchange of 346 with the catalytic lysine regenerated the PLP-imine precursor 347 and released 2-aminoacrylic acid (348), a nucleophilic enamine that reacted covalently with the cofactor-based imine 347 to produce 349.(276−282) The intermediate 348 could not be intercepted by exogenous thiols, suggesting a rapid reaction with 347. Hydrolysis of 349 was believed to lead to the irreversibly alkylated enzyme 350.(276−282) Both 339 and β-fluoro-l-alanine (351) were processed by the Escherichia coli B alanine racemase with similar partition ratios of approximately 800, although the Km values differed (Table 2).(280−284)

Scheme 44

Scheme 44. Mechanism of Inhibition of Bacterial Alanine Racemase by d-Fluoroalanine (339)
Table 2. Kinetic Constants for the Processing of l-Alanine by Escherichia coli B Alanine Racemase and Inhibition by Fluorinated Alanine Derivatives(283,284)
The mechanism of inhibition of alanine racemase by difluoroalanine (341) followed a different pathway (Scheme 45).(280,283,284) Exchange of 341 with the cofactor-bound intermediate 343 produced 352, which collapsed to 353 and then eliminated fluoride to give 354. In contrast to 346, the presence of the fluorine atom in 354 conferred sufficient electrophilicity for this intermediate to react with the catalytic lysine of the enzyme to afford 356, which eliminated the remaining fluorine to give 357.(283,284) Fluoropyruvic acid (355) was released from 354 as a side product by hydrolysis. Hydrolytic decomposition of 357 released PLP (358), leaving alanine derivatized at the catalytic lysine residue (359). However, this intermediate was hydrolytically labile and regenerated the native enzyme with the concomitant release of 2-amino-3-oxopropanoic acid (360), explaining the reversible inhibition of alanine racemase by 341. Both the d and l isomers of 341 were processed by the Escherichia coli B alanine racemase with similar Km values (116 and 102 mM, respectively), but the partition ratios were higher than for the monofluoro derivative 339 (Table 2).(283,284)

Scheme 45

Scheme 45. Mechanism of Inhibition of Bacterial Alanine Racemase by Difluoroalanine (341)
The presence of the third fluorine atom in the racemate of trifluoroalanine (342) conferred efficient inhibition of Escherichia coli B alanine racemase, with a partition ratio of 10, although the Vmax was low at <0.1 min–1.(283,284) Transamidation of 342 with 343 afforded 361, which tautomerized and lost fluoride to form the intermediate 362 (Scheme 46).(283,284) The difluorinated alkene of 362 was more electrophilic than 354 and reacted with the catalytic lysine with elimination of a second fluorine atom. This step was followed by hydrolysis, with loss of the final fluorine from 342, to give 363. This intermediate readily decarboxylated and released PLP hydrolytically to afford 364. This step left the catalytic lysine acylated by a glycine moiety and inactivated the enzyme irreversibly.(283,284)

Scheme 46

Scheme 46. Mechanism of Inhibition of Bacterial Alanine Racemase by Trifluoroalanine (342)
Fluorovinylglycine (365) followed a trifurcated pathway during processing by Escherichia coli B alanine racemase (Scheme 47).(276,277,285,286) Exchange of 365 with the enzyme lysine in the cofactor-bound 343 afforded 366, which collapsed to 367. This molecule followed the normal enzymatic pathway to lose fluoride to produce the reactive allene 368. The majority (57%) of 368 suffered hydrolytic decomposition to afford electrophilic 2-oxobut-3-enoic acid (374). However, approximately 12% of 368 reacted with the catalytic lysine to provide 369 and then 370, which was hydrolyzed to regenerate the active enzyme. Hydrolysis of 371 afforded 2-amino-3-oxobutanoic acid (372), which underwent decarboxylation to afford aminoacetone (373). The remainder (31%) of 368 reacted with a proximal noncatalytic lysine to afford the adduct 375, a Michael acceptor that reacted with the phenolic hydroxyl of a nearby tyrosine residue to generate 376. This unstable aminal intermediate degraded to produce the irreversibly inactivated enzyme 377 that retained an alkylated tyrosine residue.(276,277,285,286)

Scheme 47

Scheme 47. Mechanism of Inhibition of Bacterial Alanine Racemase by Fluorovinylglycine (365)
The phosphonic acid derivatives 378380, analogues of 339, 341, and 342, respectively, are also time-dependent inhibitors of Pseudomonas sp. ATCC 23,715 alanine racemase.(289) Compound 378 was the most potent of these derivatives, although detailed mechanistic studies of this inhibitor have not been performed.

5.5.1. Metabolism of β-Fluorinated Amines by Amino Acid Decarboxylases

β-Fluoroamino acid derivatives have also been evaluated as MBIs of the amino acid decarboxylases that are involved in the biosynthesis of aminergic neurotransmitters.(290−297) The quaternary amino acid derivatives 381, 382, and 383 are MBIs of glutamate, histidine, and dopa decarboxylases, respectively, while 384 and eflornithine (385) are inhibitors of ornithine decarboxylase.(290−297)These fluorinated analogues of the natural substrates are accepted by the decarboxylase enzymes as substrates and converted to their PLP-based imines 387, which are metabolized along the natural pathway (Scheme 48). However, the relative structural arrangement between the fluorine and the acid moiety is such that decarboxylation of 387 leads to the loss of fluoride from 388, producing the electrophilic intermediate 389. This electrophile reacts with the enzyme to produce the covalent intermediate 390. Hydrolysis of 390 ultimately captures the protein as the alkylated derivative 392, while PLP is converted to the amine 239.(290−293) The difluoromethylated derivative of ornithine, 385, is an MBI of ornithine decarboxylase that has been used clinically as an anticancer agent. Inhibition of ornithine decarboxylase by 385 prevented the biosynthesis of the downstream polyamine metabolites spermine and spermidine, which are regulators of cell growth.(294−299) Interestingly, the l derivative of 385 inhibited ornithine decarboxylase 10-fold more potently than the d isomer, although the PLP derivatives of both enantiomers were substrates of the enzyme. This outcome is surprising since the enzyme processes the l isomer of ornithine 10 000 times faster than the d isomer.(294−297) An infusion formulation of 385 has been used as part of a drug combination to treat the second stage of African trypanosomiasis (sleeping sickness) on the basis of inhibition of the ornithine decarboxylase of Trypanosoma brucei gambiense.(298−300) In addition, 385 is marketed as a topical treatment for facial hirsutism in women under the trade name Vaniqa.(300)

Scheme 48

Scheme 48. Mode of Inhibition of Amino Acid Decarboxylases by β-Fluorinated Amino Acid Derivatives 386
PLP-dependent decarboxylases are also susceptible to α-(1′-halo)vinyl-α-amino acid MBIs.(301,302) One example is d-(1-chlorovinyl)glycine (393), which inhibited the alanine racemase from Escherichia coli B.(285,303)Similarly, (1-fluorovinyl)glycine (394), an MBI of Escherichia coli B alanine racemase, also inhibited Salmonella typhimurium tryptophan synthase. Compound 395 is an inhibitor of lysine decarboxylase from the Gram-negative bacterium Hafnai alvei.(301) The proposed mode of inhibition of S. typhimurium tryptophan synthase by 394 is outlined in Scheme 49. The elimination of HF from the PLP-bound intermediate 397 was believed to give rise to the electrophilic allene 398, which reacted with a lysine residue in the enzyme to afford 399. Sequential tautomerization to 400 and 401 followed by decarboxylation afforded 402, which underwent hydrolysis and liberation of aminoacetone (373), a step that released PLP and restored enzyme function. The mode of action of the lysine decarboxylase inhibitor 395, which rapidly inactivated the enzyme with a Ki = 630 μM and a half-life of 2.8 min, has not been characterized. However, while 395 shares the natural configuration of lysine, the enantiomer 396 performed similarly as a covalent inhibitor, with a Ki of 470 μM and an inactivation half-life of 3.6 min.(301)

Scheme 49

Scheme 49. Mode of Inhibition of Tryptophan Synthase by 394
In addition to the fluorinated alkenes that were investigated as inhibitors of GABAAT (vide supra), fluorinated amino acids have also been studied. 4-Amino-3-fluorobutanoic acid (404, F-GABA) was evaluated as a probe for GABAAT and found to be a substrate but not an inhibitor of the enzyme.(222,304,305) The presence of the fluorine atom in 404 diverted the metabolic pathway away from the normal process of transamination in favor of enzymatic loss of HF that was dependent on the absolute configuration of the C–F center. Evaluation of the resolved enantiomers revealed different behaviors, with (R)-404 eliminating HF 10-fold faster and with 20-fold greater efficiency than the antipodal (S)-404. In addition, (R)-404 was a competitive inhibitor of GABAAT (Km = 49 μM), whereas (S)-404 did not inhibit the enzyme at a concentration of 1 mM. These observations were attributed to the mode of HF elimination. Experimental and theoretical studies of fluoride elimination indicated that a nonconcerted E1cb mechanism, in which the electron-deficient fluorine atom stabilized the β-anion, was preferred over a concerted E2 mechanism. On the basis of the geometries illustrated in Scheme 50a, (R)-404 could only eliminate via an E1cb mechanism because of the syn relationship between the γ-S proton in the PLP adduct (R)-405.(305,306) This elimination reaction gave (R)-406 as an intermediate. Exchange of the PLP of 407 with GABAAT released (E)-4-aminobut-3-enoic acid (408), which hydrolyzed to succinic semialdehyde (409). The other isomer, (S)-404, characterized by a trans relationship between the γ-S proton and fluorine, could avail of either an E1cb or an E2 mechanism, with the latter depicted in Scheme 50b. The profiles of (R)-404 and (S)-404 as substrates suggested that the GABAAT enzyme recognized the stereochemical relationship between the carboxylate and ammonium moieties depicted in Figure 11a. Isomer (R)-404 is a low-energy conformer because of the favorable gauche relationship between the NH3+ group and F atom. The analogous conformation for (S)-404 (Figure 11c), in which the F atom is anti to the protonated amine, has a higher energy than those depicted in Figure 11b,d.(306) Thus, because (R)-404 adopted the conformation in solution that was recognized initially by the enzyme, it was accepted more readily as a substrate. Collectively, these observations led to the conclusion that the E1cb mechanism of HF elimination predominated in both cases, with (S)-404 eliminating more slowly because of the Km rather than the kcat or Vmax parameters.(304−307)

Scheme 50

Scheme 50. (a) E1cb Mechanism of HF Elimination from (R)-404; (b) E2 Mechanism of HF Elimination from (S)-404

Figure 11

Figure 11. Conformations of (a) (R)-404 and (c) (S)-404 recognized initially by GABAAT and (b, c) the two low-energy conformations of (S)-404.

Lesogaberan (410), a GABAB agonist that was developed for the treatment of gastroesophageal reflux disease, also appears to be a substrate for GABAAT.(308,309) A metabolite profiling study in rats revealed that 410 was converted to multiple metabolites, including two that were devoid of the fluorine atom: (2-carboxyethyl)phosphinate (416) and (3-hydroxypropyl)phosphinate (417).(309) The former was the most abundant of all of the metabolites detected in urine. While the intended target of 410 was located in the periphery, autoradiography following administration of radiolabeled drug to rats revealed distribution into certain CNS structures, including the area postrema, median eminence, and pineal gland, a pattern that was reminiscent of the distribution of GABA itself.(310) This distribution pattern, together with similarities between the defluorinated urinary metabolites of 410 and those of 404, prompted the suggestion that 410 might be metabolized in the CNS. The proposed metabolic pathway for 410 is illustrated in Scheme 51. The first step is the formation of the Schiff base 411 by exchange with PLP-bound GABAAT. By analogy to the mechanism illustrated in Scheme 50, this intermediate would suffer defluorination (412) to provide the unsaturated imine 413, which would exchange with the lysine of GABAAT to release PLP and the enamine 414. Hydrolysis of 414 would afford aldehyde 415, which, although not observed directly, presumably would leave the CNS for the periphery, where it would be either oxidized to 416 or reduced to 417, the two defluorinated products that were excreted. It should be emphasized that the involvement of GABAAT in the metabolism of 410 has not been shown directly but is plausible on the basis of the similarity to the known GABAAT substrate 404 and the similarities between the tissue distributions of 410 and GABA.(310)

Scheme 51

Scheme 51. Proposed Mechanism of Defluorination of 410 by GABAAT and Further Metabolism to Give 416 and 417
Fludalanine (340) features a deuterium label that was introduced to improve the metabolic stability, and it carries the distinction of being the first such drug candidate that was advanced into clinical trials.(311) In this case, the enzyme involved in the metabolism of 340 was d-amino acid oxidase (DAAO), which catalyzes oxidative deamination to afford the toxic metabolite fluoropyruvic acid (355) (Scheme 52). The introduction of deuterium in 340 reduced the rate of oxidation 2- to 3-fold relative to the protio analogue 339. Pyruvate dehydrogenase, a thiamine diphosphate (419)-dependent enzyme, accepted 355 as a substrate and processed it initially in analogy with pyruvic acid (420). This compound was successively transformed via 421425 to the CoA ester of acetic acid (426), as depicted in Scheme 53, path a. However, the presence of fluorine in 355 led to decarboxylative defluorination of the adduct 427 to produce 428, the tautomer of 422, which could react with nucleophiles (Scheme 53, path b).(312) Alternatively, processing of 355 by lactate dehydrogenase formed fluorolactic acid (418). While toxicity associated with fluoride release by pyruvate dehydrogenase was observed in acute studies, long-term toxicology studies in the rat and rhesus monkey revealed that exposure to 418 resulted in intramyelinic vacuolation in the corpus callosum of the brain.(313) The measured levels of 418 in normal healthy volunteers afforded a therapeutic margin of approximately 10-fold. However, in patients with chronic obstructive pulmonary disease the levels of 418 were 2-fold higher, prompting the termination of 340 in 1984.

Scheme 52

Scheme 52. Metabolic Fate of 340

Scheme 53

Scheme 53. Pyruvate Dehydrogenase Uses the Cofactor Thiamine Diphosphate (419) to Effect the Decarboxylative Degradation of 355

6. α-Fluorinated Carbonyl Derivatives

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The metabolism of the mono-α-fluoroketones 40 and 119 was described earlier (Schemes 7 and 19, respectively). The former was metabolized to fluoroacetic acid (5), while the latter appeared to undergo defluorination to afford the ketone.(54,56,61,148) In another interesting example, the Ca2+-dependent large-conductance potassium (Maxi-K) channel opener flindokalner (430, BMS-204352, MaxiPost) was explored as a treatment for the sequelae of a stroke.(314,315) The metabolism of 430 illustrated the potential of an α-fluorinated carbonyl derivative to liberate fluoride metabolically. Initial indications of unusual behavior on the part of this drug were encountered during a disposition study of [14C]-430 administered intravenously to rats, where a majority of the radioactivity in the plasma could not be extracted by organic solvents.(314) Analysis of plasma proteins using gel electrophoresis demonstrated that the administered radioactivity remained associated with specific proteins, particularly albumin, following the separation. Acid-catalyzed digestion of these plasma proteins following administration of a larger dose of [14C]-430 resulted in the liberation of the lysine adduct 434 derived from desfluoro des-O-methyl [14C]-430. The bioactivation sequence proposed to explain the observation involved O-demethylation of the methoxyphenyl moiety of 430 by P450 to afford the phenol 431 as the triggering event (Scheme 54).(314) The formation of 431 set the stage for the elimination of HF to give the electrophilic o-quinone methide 432, which reacted with a Lys residue in serum albumin to give 433. Digestion of a plasma protein sample following exposure to 430 led to the isolation of the lysine adduct 434, in which the side-chain amine was bound to the same carbon atom of 430 that had been substituted with fluorine. These results suggested that 432 has sufficient chemical stability to leave the liver and reenter circulation to react with albumin.(314)

Scheme 54

Scheme 54. Proposed Bioactivation of 430 to Give Electrophile 432 and Trapping by a Lys of Serum Albumin
Whereas the structural and electronic relationship between the anisole moiety and the α-fluorinated carbonyl group set the stage for the bioactivation of 430 and the facile elimination of HF, no such activation of the α-fluorinated carbonyl motif of PF-06650833 (435) would be anticipated. The latter compound is a contemporary example of an inhibitor of interleukin-1 receptor associated kinase 4 (IRAK4) that has entered clinical development for the treatment of autoimmune diseases.(316) While 435 is reported to possess an attractive composite profile, information on the metabolic fate, reactivity, or specific benefit conferred by the α-fluorocarbonyl moiety has not been disclosed.

7. Fluorinated Aromatics

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7.1. Fluorinated Aromatics That Undergo Oxidative Defluorination or Bioactivation

Fluorine substitution is an approach that has been used commonly in medicinal chemistry to interfere with metabolic activation of aromatic rings. Under normal circumstances, oxidative metabolism of an aromatic ring may lead to the production of an arene oxide that is susceptible to nucleophilic attack by a biological nucleophile such as GSH.(1,2,21−23) The electron-withdrawing properties of fluorine can reduce the electron density of the aromatic ring and lower the rate of oxidation by P450, although the net effect of fluorination on the metabolic stability can be modest.(317,318) An example is provided by 437, the 2,10-difluoro-substituted analogue of the anticonvulsant agent carbamazepine (436), which is widely used to treat epilepsy and trigeminal neuralgia.(319)The clinical hepatotoxicity of 436 is well-documented, with several hundred cases reported in the literature. These cases appear to involve hypersensitivity or an immunological response to a metabolically generated drug–protein complex, implicating oxidative metabolism. In HLM, both arene oxidation and 10,11-epoxidation of 436 have been characterized, the latter producing a pharmacologically active but weakly electrophilic metabolite. In rat hepatocytes, 437 was not subject to oxidative dehalogenation or GSH conjugation, and while some formation of the 10,11-epoxide occurred, aromatic hydroxylation was not observed. The 2-fluoro analogue was subject to monohydroxylation as a minor pathway, and complete inhibition of aromatic hydroxylation required either difluorination (437) or monochlorination of 436.(319)
However, fluorine is a modest electron-withdrawing substituent (σp = 0.06; σm = 0.34), and aryl fluorides can be substrates for oxidative metabolism.(317,320,321) The applicable pathways include oxidation with the retention of fluorine to afford fluorinated phenols, oxidation with the loss of fluorine to form phenols, or the formation of GSH conjugates. Aromatic hydroxylation of the series of fluorobenzenes 438442by P450 was investigated in Wistar rats using 19F NMR spectroscopy, providing mechanistic evidence of a fluorine NIH shift.(322) The results demonstrated that fluorobenzenes 443 were converted in vivo to phenolic metabolites 447, in which the F atom had rearranged via an NIH-type shift (Scheme 55). However, these metabolites were minor and were overshadowed by products of ring hydroxylation that formed without loss or rearrangement of fluorine. Taken at face value, these results would suggest that oxidation accompanied by a fluorine NIH shift contributed little to the metabolism of fluorobenzenes in vivo. However, considering the reactive nature of the presumed epoxide intermediate (439), some of this material may have been lost to an alternative metabolic pathway. The latter possibility was supported by incubations in liver microsomes that showed the formation of a substantial amount of an NIH-shifted product during the metabolism of 1,4-difluorobenzene (438) in vitro.(322) The addition of GSH and liver cytosol to microsomal incubations lowered the relative abundance of the NIH-shifted phenolic metabolites by 26%, indicating GSH conjugation as a possible competing pathway. Thus, the low yield of fluorine NIH-shifted products during the metabolism of fluoro-substituted benzene derivatives in vivo can, at least in part, be ascribed to alternative pathways for metabolism of the epoxide. GSH conjugation is one potential alternative pathway, facilitated by the enhanced reactivity of fluorinated arene oxides. These fluorinated arene oxides exhibit lower calculated ELUMO values than those substituted by chlorine, implying faster reactions between fluorine-substituted arene oxides and nucleophiles.(322)

Scheme 55

Scheme 55. Aromatic Oxidation Accompanied by the NIH Shift of Fluorine in Fluorobenzenes
In a metabolism study that exemplified a fluorine NIH shift, urinary metabolites were profiled following oral administration of the quinoxaline-based HIV-1 non-nucleoside reverse transcriptase inhibitor GW420867X (448) to rabbits, mice, and humans.(323) As captured in Scheme 56, 448 was metabolized extensively on the fluorophenyl ring to form hydroxylated metabolites and glucuronide conjugates in all species. The phenolic metabolites and corresponding glucuronide conjugates were isolated by semipreparative HPLC, and the relative proportions of fluorine-containing metabolites were determined by 19F NMR analysis. The NMR spectra of the isolated metabolites 449 and 450 indicated that the fluorine atom on the phenyl ring had undergone an NIH shift, whereas the composite analytical data of a third metabolite 451 implicated oxidative defluorination as a competing pathway that could originate from the epoxide precursors of 449 and 450. The characterization of the NIH-shifted metabolites in urine from the preclinical species helped facilitate the subsequent identification of these metabolites in human plasma in the clinical trials.(323)

Scheme 56

Scheme 56. Metabolism of 448, a Quinoxaline-Based Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase
The fluorination pattern of the hedgehog pathway inhibitor 452 was designed to reduce the electron density of the benzyl moiety and thereby lower its susceptibility to oxidative metabolism.(324) However, metabolite profiling studies with 452 in HLM identified a metabolite, proposed to be the quinone methide 454, that formed during oxidative defluorination of the benzyl moiety. Quinone methide 454 was sufficiently stable to be separated and characterized on a small scale by LC–MS, but this technique did not allow the quinone methide regiochemistry and olefin geometry to be determined (Scheme 57).(324) In reaction-phenotyping studies, metabolic activation of 452 was NADPH-dependent and catalyzed primarily by CYP3A4. One mechanism of bioactivation that was proposed relied on epoxidation of the fluorophenyl ring to afford 453 (Scheme 57). This arene oxide would rearrange to 454, a compound that is stabilized by resonance delocalization of the lone pair of electrons on the piperazine N atom. An alternative proposal envisioned H atom abstraction by P450 from the benzylic site and subsequent oxidation of the delocalized radical.(324) In addition to the quinone methide 454, a GSH adduct of undefined regiochemistry, 455, was identified along with a hydroxylated analogue of this metabolite.(325) Consideration was also given to the potential for the GSH adduct 455 to arise by direct reaction with the epoxide intermediate 453.

Scheme 57

Scheme 57. Potential Metabolic Activation Pathways of the Hedgehog Pathway Inhibitor 452
Tegobuvir (456, TGV) is a mechanistically interesting inhibitor of HCV RNA replication that was discovered through a phenotypic screening approach assessing subgenomic viral replication in replicons.(326) Although this compound was advanced into clinical trials, where it demonstrated antiviral activity in patients infected with genotype 1 chronic HCV infection, its mode of action was enigmatic. While the resistance mutations that arose in response to exposure to 456 in the replicon system could be mapped to the NS5B polymerase protein, the compound failed to inhibit NS5B enzymatic activity in biochemical assays, a conundrum that suggested a more complex antiviral mechanism. Studies to elucidate the mechanism of action revealed that treatment of HCV subgenomic replicon cells with 456 resulted in a modified form of the NS5B protein that exhibited altered mobility on a Western blot SDS-PAGE gel. The modified protein was characterized further as an adduct carrying an additional mass of 820 Da. Formation of the adduct protein did not require the presence of other HCV proteins but was dependent on both functional CYP1A1 enzyme activity and the presence of cellular GSH. Further insight into the inactivation mechanism was provided by the results of mass spectrometric analysis of NS5B that had been purified from a heterologous expression system and treated with 456.(326) The NS5B protein adduct afforded by this process (462 and/or 463) was characterized as a GSH conjugate of defluorinated 456 that had reacted with a Cys residue of the enzyme. On the basis of the experimental observations, a metabolic pathway was proposed involving epoxidation of the fluorobenzene ring of 456 as the triggering event (Scheme 58). Ring opening of the epoxide of 457, facilitated by delocalization of the pyridine N atom electron lone pair, would afford an intermediate that could degrade by the loss of fluoride. This process would produce the highly electrophilic ketone 458, which has multiple potential sites for adduction with GSH. GSH addition by pathways a and b followed by tautomerization would afford the phenolic adducts 459 and 460. However, GSH addition by pathway c would result in the production of the cyclic dienone 461, which could tautomerize to a phenol. This dienone would retain two exposed electrophilic centers capable of reacting with a Cys residue of HCV NS5B, with 462 and/or 463 representing the observed protein adduct.(326) While the specific residue of HCV NS5B that was decorated by 461 was not identified, Cys366, which is proximal to the active site of the enzyme and has been shown to be susceptible to reaction with covalently acting HCV NS5B inhibitors, was a plausible candidate.(327)

Scheme 58

Scheme 58. Proposed Mode of Inhibition of HCV NS5B Polymerase by 456 in HCV Replicons
The BACE-1 inhibitor 464, which incorporates a 5-fluoro-2-aminopyrimidine heterocycle, was identified as a promising lead on the basis of its performance in cell-based assays but was associated with CYP3A4 TDI that was traced to metabolic activation of the fluorinated heterocycle.(328) Studies revealed that the bioactivation of this moiety resulted in an oxidative defluorination to give the GSH conjugate 467 and the pyrimidin-5-ol 468, a metabolic pathway that was responsible for the observed TDI (Scheme 59). The proposed metabolic pathway relied on oxidation of the fluoropyrimidine ring to afford an epoxide intermediate followed by reaction with GSH to give an unstable fluorohydrin adduct. This adduct would lose HF to afford 466, which would then tautomerize to the observed product 467. Alternatively, epoxide ring opening with loss of fluoride, as the result of anchimeric assistance by the pyrrolidine N atom, would produce a highly electrophilic quinone iminium derivative that could either add GSH to produce 467 or be reduced to give 468.(328) Further support for this postulate was provided by studies of the fluorophenyl and unsubstituted pyrimidine analogues, neither of which resulted in CYP3A4 TDI (IC50 > 30 μM). Additional structure–liability studies confirmed that dual substitution at the 4- and 6-positions of the 5-fluoropyrimidine ring was sufficient to ameliorate the TDI. This protective effect was exemplified by the 4,6-dimethyl-5-fluoropyrimidine analogue 465, which demonstrated 10-fold weaker inhibition of CYP3A4 relative to 464.(328)

Scheme 59

Scheme 59. Proposed Bioactivation Pathway for the BACE-1 Inhibitor 464, a 5-Fluorinated Pyrimidine Derivative Associated with CYP3A4 TDI
Other fluorinated drugs that release fluoride in vivo include the anesthetic agent sevoflurane (98) (vide supra)(132,334) and voriconazole (469), an antifungal agent that became the subject of safety concerns following the observation of periostitis in a heart transplant patient receiving long-term therapy.(329) A group of 10 post-transplant subjects who received 469 at an oral dose of 200 mg twice daily for at least 6 months were compared to a control group of 10 post-transplant subjects who were exposed only to environmental sources of fluoride (e.g., in drinking water and toothpaste). The levels of fluoride in the plasma of the group treated with 469 were found to be elevated relative to the control cohort (14.32 vs 2.54 μM; P < 0.001). Although renal clearance of fluoride is related to the glomerular filtration rate, renal function was not predictive of plasma fluoride levels. These concentrations remained significantly higher in the group treated with 469 even after adjusting for the levels of the immunosuppressive calcineurin inhibitors that are commonly used to treat transplant patients.(329) Half of the subjects treated with 469 showed evidence of periostitis. Two of these patients also had exostoses (periosteal bone growths), a known symptom of fluorosis caused by the strong affinity of fluoride for bones. In patients with evidence of periostitis, discontinuation of 469 relieved their pain and reduced the blood levels of both fluoride and alkaline phosphatase. Earlier studies of lung transplant patients exposed to 469 had also described cases of periostitis, although fluoride levels were not measured.(330,331) While studies of the metabolism of 469 had demonstrated that 5% of a dose of the drug was metabolized to release fluoride in humans (but not in mouse, rat, rabbit, guinea pig, or dog), those studies had failed to account for all of the excreted metabolites of the drug.(329,332,333) Collectively, these findings suggested that the adverse events described were elicited by the release of fluoride from 469 as a consequence of hepatic oxidative metabolism, leading to variably elevated fluoride levels in plasma after extended treatment. Metabolism studies identified the fluoropyrimidine moiety as one site of oxidative metabolism, while the difluorophenyl ring appeared to be inert.

7.2. Fluorinated Aromatics That Undergo Defluorination via Nucleophilic Substitution

In some chemical environments, aromatic C–F bonds may be subject to spontaneous or enzymatic ipso defluorination via an SNAr substitution reaction. An example of this phenomenon is provided by perfluorophenyl rings, which are predisposed by an excess of electron-withdrawing substituents to direct attack by nucleophiles such as GSH. Incubation of the DPP4 inhibitor 470 in GSH-enriched rat hepatocytes and liver microsomes led to the production of the four GSH conjugates 471474.(334)The formation of 471, a conjugate of undefined regiochemistry, occurred in phosphate buffer and was rationalized as the product of direct nucleophilic displacement of fluoride by GSH (Scheme 60, pathway a). Interestingly, the formation of 471 was enhanced in both phenobarbital- and dexamethasone-induced RLM, suggesting that GSTs, which are also induced by phenobarbital and dexamethasone in rats, may have been involved in catalysis.(334) The formation of 472474 was NADPH-dependent and catalyzed by recombinant rat CYP3A1 and CYP3A2, although again, the regiochemistry of GSH adduction was speculative. The generation of 472 was hypothesized to occur either by oxidative defluorination of 471 or by a reaction involving the formation of the arene oxide 475, which captured GSH and eliminated fluoride to afford 476 as an initial intermediate (Scheme 60, pathway b). Reduction of the carbonyl group would give 477, and loss of HF would then afford 472. The quinones 478 and 479were proposed as plausible metabolic precursors to 473 and 474, respectively, although alternative pathways to these metabolites were also considered.(334)

Scheme 60

Scheme 60. Proposed Metabolic Pathways of the Pentafluorophenyl-Based DPP4 Inhibitor 470 to give 471 and 472 (the Regiochemistry of GSH in 471 and 472 Was Not Determined)
Another pentafluorinated aromatic derivative that was reactive toward thiols was the β-tubulin inhibitor T138067 (480).(335−337)This compound inactivated the β1, β2, and β4 isotype proteins by reacting with the conserved Cys239 to form a covalent adduct, resulting in microtubule degradation and cell-cycle arrest. The GSH conjugate 481 and derivatives 482 and 483 were isolated from tissue culture samples, from mouse, rat, dog, and human liver slices, and from the bile of mice treated intravenously with 480. The regiochemistry of fluorine displacement in 481 was established by 19F NMR analysis, which revealed only three resonance signal groups. Substitution was catalyzed in vitro by GSTα, GSTμ, and GSTπ, all of which are widely expressed in tissues, including those harvested from tumors. At physiological pH in the absence of GST enzymes, 480 did not react with GSH, indicating that the formation of 481 relied on metabolism and not just intrinsic reactivity.(335−337)
The 8-fluorotriazolopyridine-based c-Met inhibitors 484 and 485 were susceptible to displacement of fluorine by GSH in RLM, causing concern over the potential for GSH depletion and increased oxidative stress.(338) In addition, major metabolic pathways involving GSTs might lead to variable pharmacokinetics among human subjects due to differences in the expression of GST isoforms within the population. While removal of the C-8 fluorine atom in 484 and 485 would have avoided this metabolic pathway, this atom was an important contributor to potency. Hence, attention shifted toward modifying other parts of the molecule. It was hypothesized that the electrophilic character of the fluorinated triazolopyridine core could be attenuated by replacing the benzylic fluorine atoms with small alkyl groups and/or hydrogen atoms. This idea resulted in the identification of 486, which formed negligible amounts of GSH conjugates in bile-duct-cannulated rats and exhibited the best overall combination of potency and pharmacokinetic properties. The introduction of the 2-methoxyethoxy side chain also provided an alternative soft spot that redirected metabolism away from the core heterocycle in liver microsomes.(338)

7.3. 2-Fluoropyridine Derivatives

2-Fluoropyridine derivatives have been examined broadly in medicinal chemistry as a means of influencing pyridine basicity, interfering with biotransformation to the pyridine N-oxide, and reducing P450 inhibition and (when labeled with [18F]) for use in PET imaging.(339−345) Representative 2-fluoropyridine derivatives that have been advanced into clinical trials include the acetylcholine release enhancer DMP-543 (487), the AMPA receptor positive allosteric modulator 488, the CNS-penetrant phosphodiesterase-1 inhibitor 489, and the insulin-like growth factor receptor kinase inhibitor BMS-754807 (490).(346−348)While 2-fluorinated pyridines have been exploited as reactive electrophilic intermediates in organic synthesis, there is little evidence to implicate intrinsic reactivity in biological systems as a problem. Nonetheless, their presence may result in the adoption of a cautionary stance.(349) Chemically, the hydrolytic loss of fluoride from 2-fluoropyridine derivatives can proceed via two mechanisms depending on the chemical environment: rings that are not activated by the presence of an electron-withdrawing substituent typically react via protonation of the ring N atom, whereas analogues substituted with strong electron-withdrawing substituents are more susceptible to SNAr substitution with expulsion of fluoride from the intermediate Meisenheimer complex.(350) While the reactivity of 2-fluoropyridine derivatives toward biological nucleophiles has not been studied in detail, the reactivity of a series of 2-chloropyridines toward ipso substitution by GSH in RLM, conditions that capture microsomal GST-1 activity, has been assessed and provides some guidance.(351) 2-Chloropyridine (491) was stable toward GSH in both the presence and absence of microsomal GST-1, with only low intrinsic reactivity observed (<5% transformed under the assay conditions). Indeed, appreciable SNAr reactivity catalyzed by microsomal GST-1 was observed only with the additional electronic activation afforded by nitro substitution of the ring (Table 3).(351) Thus, 2-chloro-3-nitropyridine (493) reacted with GSH in RLM at a rate of 236 nmol min–1 mg–1, translating to 100% depletion of the molecule over a 30 min incubation period. For comparison, 491 was consumed at a rate of less than 2 nmol min–1 mg–1 and 1-chloro-2-nitrobenzene (492) at a rate of 6.8 nmol min–1 mg–1. Other electron-withdrawing substituents at C-3 (494, 495) promoted the SNAr reaction, although less effectively than the nitro substituent. As might be anticipated, the electron-donating substituents in 496499 mitigated the chemical reactivity. Notably, the background reactivity rate of 493 was low but measurable, with approximately 5% converted to the adduct in phosphate buffer, suggesting that modification of 2-halopyridines was driven primarily by metabolism.(351)
Table 3. Reactivity of Halogenated Aromatic and Heteroaromatic Rings toward GSH in RLMa
compdXRreactivity rate (nmol min–1 mg–1)bsubstrate depletioncΔG (kcal/mol)
491NH<2 39.6
492CHNO26.8 ± 1.1 24.6
493NNO2236 ± 8100 ± 019.6
494NCF3 31 ± 630.0
495NCl 26 ± 433.9
496NOCH3 17 ± 840.8
497NCH3 14 ± 540.9
498NNH2 <539.7
499NOH <532.6
a

Substrate (50 μM) was incubated with RLM (1 mg of protein/mL), GSH (5 mM), and MgCl2 (3 mM) in phosphate buffer (0.1 M; pH 7.4) at 37 °C. (Note: no NADPH was used in these experiments.) ΔG represents the calculated difference in Gibbs free energy between the ground state of the substrate and a Meisenheimer complex transition state derived by addition of thiolate.

b

Incubations were of varied duration (1 to 40 min).

c

Samples were incubated for 30 min; the data presented are the percentage decreases of the substrate, and the values are means ± SD (n = 3).

Linopirdine (500), the predecessor to 487, was subject to N-oxidation in rats, dogs, and humans to afford the N-oxides 501 and 502 (Scheme 61).(352−354) The fluorinated derivative 503 was explored for its potential to resist this metabolic pathway. Synthetic studies with 503 failed to produce N-oxides despite the use of strong oxidizing reagents that included CF3CO3H, suggesting considerable intrinsic resistance toward oxidation and, by extension, downstream conjugative metabolism. N-Oxidation enhanced the reactivity of 2-halopyridines, and 2-fluoropyridine 1-oxide reacted with dipeptides at room temperature via displacement of fluoride by the terminal amino moiety.(355,356) Thus, the occurrence of the N-oxidation pathway in vivo for 2-halopyridines would create concern over the potential for generation of reactive metabolites.

Scheme 61

Scheme 61. Formation of N-Oxide Metabolites 501 and 502 from 500 In Vivo
DMP-543 (487) emerged from an effort seeking to improve on the properties of the oxindole 500. The fluorine atoms were included to improve brain exposure and reduce the propensity for N-oxide formation that had been observed in studies of 500. While 487 was advanced into clinical trials as a potential treatment for Alzheimer’s disease, its high potency resulted in a low projected human dose of 25 μg, which presented unique challenges in the identification of a stable and uniform formulation.(357) Although the pure form of 487 was stable for several years, the tablet formulation was characterized by degradation to the monopyridone 504 (relative abundance of 0.5%) upon storage for 6 months at 40 °C and 75% relative humidity. The chemical degradation was dependent on the temperature, pH, and excipient composition but not the drug concentration. The likely degradation mechanism was informed by prior solution stability studies that had revealed sequential hydrolysis of the fluorine substituents under acidic conditions but good stability for 51 days at 80 °C in phosphate (pH 6.6) and borate (pH 9.2) buffers. These observations prompted the suggestion that the addition of a basic excipient might enhance the chemical stability.(358) This approach was effective, as a revised formulation that included 1% magnesium stearate (a base and lubricant) and lactose monohydrate (a diluent) suffered <0.1% degradation under the same storage conditions described above.
The discovery of 488 was informed by experience with the lead compound 505, which was characterized by acceptable potency and receptor activation but poor brain penetration. The latter issue was attributed to the high polar surface area (PSA) of 92 Å2 and efflux by P-gp, problems that could not be resolved by manipulation of the methanesulfonamide moiety.(346) The pyridine analogue 506 exhibited considerably weaker binding affinity, but its activation of AMPA receptors was comparable to that of cyclothiazide, a reference standard. While 506 demonstrated the targeted low PSA (59 Å2) and clogP (2.3) values, it also exhibited moderate clearance in RLM and potent inhibition of CYP1A2 (IC50 = 600 nM). The targeted physicochemical parameters limited the scope of substitution of the pyridine ring to halogen and alkyl substituents, and the 2- and 6-fluoro compounds 507 and 508 emerged as compounds with preferred profiles. This substitution pattern addressed the CYP1A2 inhibition and slightly increased the clogP value from 2.3 to 2.6 while preserving a low PSA.(346) Resolution of 508 revealed that biological activity resided with the S isomer 488 (pEC50 = 5.6, asym max = 107%), which demonstrated low turnover in RLM and HLM. The high membrane permeability of 488 coupled with an absence of efflux by P-gp contributed to the observed 61% oral bioavailability in rats and good CNS penetration, properties that subtended its efficacy in rat models of cognition. Metabolism studies of 488 in rat, dog, monkey, and human liver microsomes revealed five minor metabolites, of which three resulted from hydroxylation of the indane ring and two from hydroxylation of the isopropyl and aryl moieties (Figure 12). No metabolic changes to the fluoropyridine ring were described, and there was no apparent evidence of genotoxicity in vitro. In clinical studies, the pharmacokinetic profile of 488 revealed rapid absorption and a surprisingly long apparent half-life of 107 to 168 h.(346)

Figure 12

Figure 12. Metabolic soft spots associated with 488 in liver microsomes.

The potent PDE-1 inhibitor ITI-214 (489) (Ki PDE-1 = 5.8 pM) is being evaluated clinically for its potential to address movement disorders, including Parkinson’s disease, and the cognitive deficits associated with Alzheimer’s disease, schizophrenia, and attention deficit hyperactivity disorder.(347) Compound 489 exhibited higher log D values (4.41 at pH 7.4 and 1.27 at pH 1.7) than the non-fluorinated variant 509 (3.54 at pH 7.4 and −0.58 at pH 1.7), reflecting the reduced basicity of the pyridine nitrogen. While this difference was accompanied by reduced solubility, the oral pharmacokinetics of 489 in mice and rats was superior to that of 509, with a 10-fold higher plasma area under the curve (AUC) in mice and a 20-fold advantage in CNS penetration. Although preclinical profiling studies of 489 have been described, details of the metabolism have yet to be disclosed.(359)
A medicinal chemistry effort exploring 4-aryl-N-arylcarbonyl-2-aminothiazoles as Hec1/Nek2 inhibitors, which exhibited antiproliferative activity against several cancer cell lines, offered the opportunity to compare the properties of the unsubstituted pyridine derivative 510 with those of the 2-fluoro analogue 511.(360)While the in vitro potencies of the two compounds toward the MB231 breast cancer cell line were similar, 511 was characterized by 2-fold lower clearance and an almost 2-fold higher AUC following intravenous administration to rats. The low clearance of 511 in vivo reflected low metabolic clearance in RLM, in which the half-life was approximately 340 min. However, following oral administration to rats (20 mg/kg) in a vehicle of 1% methylcellulose in H2O, the bioavailability of 511 (4.6%) was lower than that of 510 (12.4%). This difference was attributed to the lower basicity and aqueous solubility of 511 (190 nM in phosphate buffer containing 1% DMSO at pH 7) relative to the unsubstituted pyridine analogues. This problem was solved by formulating 511 in a mixture of 5% DMSO, 10% cremophor, and 85% H2O, which increased the oral bioavailability in the rat to 22.7%, a result consistent with solubility-limited absorption.(360)
Analogous to the circumstance with the 2-fluoropyridine rings, there is scant information available on the potential for problems with 4-fluoropyridine derivatives. However, some 4-chloro- and 4-bromopyridines have been studied, which may allow inference about potential chemical reactivity and metabolism. These compounds are usually stable during incubations with GSH under ambient conditions, but SNAr substitution of the halide can be catalyzed by GST. The 4-halopyridines 512 and 513were discovered by fragment screening to be MBIs of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that regulates nitric oxide production by catabolizing Nω,Nω-dimethyl-l-arginine, an endogenous inhibitor of nitric oxide synthases.(361) Mutation data supported a mechanism of inhibition that was dependent on the reaction of these compounds with the catalytic Cys249 of DDAH via an SNAr process, in which the pyridinium form of the molecule was stabilized in the active site by the proximal Asp66 (Scheme 62). More precise details of the mechanism were discerned by a combination of X-ray crystallographic data and modeling studies, which further illuminated the role of Asp66. This analysis suggested the involvement of a catalytic triad (Cys249, Ser248, Glu65) that activated the thiol moiety of Cys249 of DDAH. The Cys249 residue was characterized by an unusually high pKa value of ∼8.8, reflecting the dependence on a catalytic triad.(362)

Scheme 62

Scheme 62. Mechanism Proposed to Explain the Reaction of 513 with DDAH
The semisynthetic spectinamide antibiotics, represented generically by 514, are derived from spectinomycin (515) and exhibit activity toward multidrug-resistant tuberculosis strains. The 4-chloropyridine moiety of certain representatives of this class, including 516, were subject to GSH conjugation via an SNAr process in human and rat S9 fractions (Scheme 63).(363) The rates of GSH conjugation were dependent on both the species and the substitution pattern on the pyridine ring. The calculated pKa values of the pyridyl nitrogen atoms also correlated well with the extent of GSH displacement. Less basic pyridines were more stable, consistent with a mechanism involving enzymatic protonation of the heterocycle that set the stage for attack of GSH at C-4. Non-halogenated and C-3-halogenated pyridines were stable toward conjugation. Similarly, a 5-fluoro-4-chloro-substituted pyridine was also stable, a finding that was attributed to the reduced basicity of the heterocycle.(363)

Scheme 63

Scheme 63. Metabolism of 4-Chloropyridine-Based Spectinamide Derivatives 516 Catalyzed by GST

7.4. Fluorinated Purine Derivatives

GSH conjugates of 6-halopurines are substrates of the multidrug resistance-associated protein 1 transporter (MRP1) and serve as useful probes for the study of this efflux pump.(364−366) (MRP1 is encoded by the gene ABCC1 and should not be confused with P-gp, encoded by ABCB1.) The success of this approach, which is based on the metabolite extrusion method, depends on the rapid conversion of CNS-permeable 6-halopurines to their GSH conjugates in the CNS followed by transport of these metabolites back across the membrane. The labeled 6-bromo-7-methyl-7H-purine (523) (Table 4) showed early promise as a reagent for these studies. However, in order to identify an improved probe and explore differences among nonclinical species, the rates of reactivity of other 6-halo-7-methyl-7H-purines and 6-halo-9-methyl-9H-purines toward GSH were measured in phosphate buffer and in brain homogenates (mouse, rat, and rhesus monkey) that contain GSTs.(366−369) The results revealed that in both series, the fluoro derivatives (517 and 521) were more intrinsically reactive toward GSH in buffer than their higher halogen homologues 518520 and 522524, respectively, while the 6-halo-7-methyl-7H-purines 521524 were more reactive than the 9-methyl isomers 517520 (Table 4). Rates of conversion were higher in brain homogenate but varied by species. A high ratio of the rate of enzymatic to intrinsic displacement was considered to be advantageous in these studies, since it would minimize nonspecific displacement by thiols in vivo.(366,367)
Table 4. Intrinsic and GST-Catalyzed Rates of Reactivity between Halo-Substituted Purines and GSHa
a

knon is the rate constant for the non-enzymatic process in phosphate buffer (0.1 M, pH 7.4) supplemented with GSH (2 mM).

b

kenz is the rate constant for the enzyme-catalyzed process in cerebral cortical homogenate supplemented with GSH (2 mM).

The series of 6-halogenated 2′,3′-dideoxypurine (ddP) derivatives 525528 was studied in an effort to identify a prodrug of 2′,3′-dideoxyinosine (didanosine, ddI, 529), a premise that would require these compounds to be recognized as substrates of adenosine deaminase (Table 5).(370) An experiment assessing the activities of these compounds toward HIV-1 infection in cell culture revealed that the trend of antiretroviral potencies in the series (F > Cl > Br > I) reflected the half-lives in whole blood (F < Cl < Br < I) (Table 5).(370,371) Additionally, the increased lipophilicity of these halogenated purines relative to 529 provided a means of selectively targeting the virus in the CNS, in which rates of conversion were 10-fold higher in brain homogenates than in whole blood, potentially offering improved treatment of HIV-1-related neurological abnormalities. The half-lives and rates of conversion in these matrices are provided in Table 5.(371) The 6-fluoro derivative 525 caused lethargy and labored breathing in rats and was not evaluated further, as the therapeutic margins were deemed to be too narrow. The 6-chloro analogue 526 provided a balance of properties, delivering substantially higher concentrations of 529 to the brain than an equivalent intravenous infusion of the parent nucleoside.
Table 5. Kinetics of Hydrolysis of 6-Halo ddP Analogues 525528 by Adenosine Deaminase to Give 529 at 37 °C and Half-Lives in Blood and Brain Homogenate
    t1/2 (min)
compdXKm (M)Vmax (M/min)bloodbrain tissue
525F7.2 × 10–41.4 × 10–43.50.46
526Cl0.0174.4 × 10–527019
527Br0.0164.0 × 10–528020
528INDND1690178
  whole bloodabrain tissuea
compdXk1 (min–1)k2 (min–1)Fk1 (min–1)k2 (min–1)F
525F0.150.130.541.51∼01.00
526Cl3.0 × 10–37.4 × 10–30.280.032∼01.00
a

k1 is the rate of conversion to ddI by adenosine deaminase. k2 is the rate of conversion to ddI by other unknown sources. F is the total fraction of prodrug converted to ddI.

A similar prodrug approach was explored in the context of 531533, 6-substituted derivatives of acyclovir (530), and 535537, 6-substituted derivatives ganciclovir (534), which were anticipated to be susceptible to conversion to the corresponding guanines by adenosine deaminase.(372−374) In both series, the fluoro derivatives (531 and 535) were superior substrates of the enzyme compared with either the chloro (532 and 536) or amino (533 and 537) analogues (Table 6). The isopropyl ester 538, a double prodrug of 530, provided at least 51% conversion to the parent drug following oral dosing to rats based on the recovery of 530 from urine over 48 h. This concept was extended to 540, which performed similarly as a prodrug of penciclovir (539) in vivo.(375)
Table 6. Kinetics of Hydrolysis of 6-Substituted Analogues by Adenosine Deaminase to Afford Either Acyclovir (530) or Ganciclovir (534)
In a structurally related purine-like chemotype, the mTor inhibitor 541 was relatively stable in HLM but metabolized in human hepatocytes to the GSH conjugate 542.(376) Studies of similar compounds also demonstrated biotransformation in hepatocytes at the same aromatic carbon atom, with the higher chloro- and bromo-substituted homologues also undergoing direct displacement by GSH and the lower hydrogen-substituted homologue experiencing oxidation by aldehyde oxidase. While the involvement of GST in the former displacement reaction was not investigated, the metabolite profiles of these compounds suggested a degree of reactivity that was sufficient to justify deprioritization of this series from further inquiry.(376)

7.5. Fluorinated Alkyl Substituents

Carmegliptin (543) is a potent and long-acting DPP4 inhibitor that was studied clinically for its potential to treat type-2 diabetes.(377,378) Early analogues in the series were characterized by a tricyclic aminobenzo[a]quinolizine scaffold and a structurally distinct S1 recognition motif, with the fluoromethyl-substituted analogue 544 shown to bind to human DPP4 by X-ray crystallography.(377) This compound also offered 10-fold improved inhibition (IC50 = 0.5 nM) over the corresponding CH3 analogue, suggesting that potency and properties in the aryl series could be modulated through optimization of the S1 substituent. Although 544 exhibited the best fit in the S1 pocket, this compound was found to be Ames-positive and clastogenic in the micronucleus test.(377,378) Installing a more polar pyridine ring in the S1 ligand position led to 545, a potent DPP4 inhibitor with improved composite properties. However, additional benefits were realized by tuning the polarity across this S1 substituent, resulting in 543. Uncharacteristic of drugs in this class, 543 was found to undergo both renal and hepatic excretion, suggesting that it might be useful in patients with renal impairment. The metabolism of 543 does not appear to involve any specific changes to the fluoromethyl group, and while phase 1 and 2 clinical studies indicated its suitability as a safe oral antidiabetic agent with once-daily administration, development was terminated.(379)
The [18F]-monofluoromethyl-substituted thiazole SP203 (546) was developed as a radioligand for imaging of mGluR5 receptors in the brain.(380) However, in both the rat and monkey, radioactivity was observed in bone, indicating release of [18F]fluoride. To explore the mechanism of defluorination, both [18F]-546 and its non-radiolabeled analogue were administered to rats, and brain homogenates and urine were analyzed for metabolites. In those studies, radio-HPLC was used to detect [18F]fluoride as a major metabolite in both matrices. In a subsequent incubation with brain homogenate ex vivo, 546 exhibited a half-life of only 20 min and was converted to a major metabolite, whereas no such metabolism was apparent in whole blood ex vivo. Analysis of the brain extract by LC–MS/MS identified the GSH conjugate 547 and the N-acetylcysteine derivative 548. Only the latter was detected in rat urine, indicative of complete processing of 547 along the mercapturic acid pathway. Thus, GSH conjugation of the 2-fluoromethyl group of 546 was responsible for defluorination in rats.(380)
The bioactivation of aryl fluoromethyl and difluoromethyl groups can be leveraged for the design of MBIs of enzymes, an approach that has been explored in the context of inhibitors of tyrosine hydroxylase.(381) Tyrosine hydroxylation is the rate-limiting step in catecholamine biosynthesis, and α-methyl-l-tyrosine (metyrosine, 549) is a tyrosine hydroxylase inhibitor that is approved for the treatment of hypertensive patients who have a pheochromocytoma, a rare adrenal tumor associated with elevated catecholamine levels.(382)dl-2-Fluoromethyl-p-tyrosine (550) and dl-2-difluoromethyl-p-tyrosine (551) were designed as MBIs of tyrosine hydroxylase on the premise that oxidation of these compounds to a phenol by the enzyme would set the stage for loss of HF and the generation of reactive quinone methides (Scheme 64).(381) Both 550 and 551 were characterized as competitive inhibitors of purified bovine adrenal tyrosine hydroxylase. However, additional biochemical data have not been reported, and it remains unclear whether these compounds do indeed act by the intended pathway.

Scheme 64

Scheme 64. Postulated Mechanism of Inactivation of Tyrosine Hydroxylase by 550 and 551
While benzylic fluorides are chemically more reactive than the difluoromethyl and trifluoromethyl homologues toward substitution reactions, there are circumstances where aryl difluoromethyl and trifluoromethyl moieties are reactive.(27) For example, the non-enzymatic hydrolysis of 6-difluoromethyltryptophan (552) to 6-formyltryptophan (553) occurred slowly (k = 0.0039 min–1) under neutral conditions.(383) However, the reaction was accelerated 104-fold when the pH was raised to deprotonate the indole NH (Scheme 65, path a). In this series, the solution stability of homologous 6-substituted indoles increased in the order of CH2F < CHF2 ≪ CF3. Tryptophanase, a PLP-dependent enzyme that converts 552 to 555, apparently did not facilitate this reaction since there was evidence of protein-dependent conversion of the difluoromethyl group. Rather, tryptophanase activated the aromatic ring by protonation at C-3, leading to the release of the 6-(difluoromethyl)-1H-indole (555) (Scheme 65, path b), a process that would preclude anion formation and fluoride elimination. Hence, the enzyme catalyzed the catabolism of 552 in much the same manner as it processes tryptophan, leading to the formation of 555 and 556 via the PLP-derivative 554. The latter complex was then subject to hydrolytic decomposition, yielding pyruvic acid (420) and NH3.(383) However, this pathway required the heterocyclic system of the substrate to be electron-rich, thereby slowing turnover for substrates carrying an electron-withdrawing group at C-6.

Scheme 65

Scheme 65. Base-Catalyzed Reaction (Path a) and Trytophanase-Mediated Metabolism (Path b) of 552
The reactivity of the 2-difluoromethylphenol moiety was leveraged in the design of MBIs of neuraminidases intended for the treatment of influenza virus infection.(384) These glycoside hydrolases cleave sialic acid moieties from glycoproteins and regulate viral replication. 2-Difluoromethylphenolic glycosides were first reported in the 1990s as glucosidase inhibitors, and similar approaches have been applied in the design of inhibitors of a range of glycosidases, including neuraminidases, galactosidases, N-acetyl glucosaminidase, and other hydrolases that have extended to phosphatases, sulfatases, and proteases. 2-Fluoromethylphenolic glycosides, represented by 557 (Scheme 66), were stable until the glycosidic bond was cleaved, and 4-substituted isomers behaved similarly. Following neuraminidase-mediated cleavage of 557, the resulting phenolate 558 was configured to eliminate fluoride, a reaction that yielded the o-quinone methide 559, which inactivated the enzyme by forming the covalent adduct 560.(384) Characterization of a library of synthetic 2-difluoromethylphenyl sialosides enabled the identification of potent and selective reagents that labeled neuraminidases according to this mechanism. Constituent members of these libraries differentially inhibited two neuraminidases, Vibrio cholerae neuraminidase and human neuraminidase 2, and the most potent inhibitors of each neuraminidase were selected for additional study. A kinetic analysis of these inhibitors demonstrated that synthetic modifications to the aglycone moiety resulted in improvements to the Ki with little change in other kinetic constants, including kinact and the half-life.

Scheme 66

Scheme 66. Mechanism-Based Inactivation of Neuraminidases by Sialoside Substrates Bearing Difluoromethylphenol Groups
Mechanism-based fluorescent labeling of β-galactosidase by 2-difluoromethylphenyl aglycones has also been demonstrated in the context of proteomics applications.(385) One such compound, 4-[5-(dimethylamino)naphthalene-1-sulfonamido]-2-(difluoromethyl)phenyl β-galactopyranoside (561) (Figure 13), was used to tag the catalytic sites of several bacterial galactosidases with a fluorescent dansylated aglycone that was captured using an antidansyl antibody and characterized by MALDI-TOF/TOF tandem mass spectrometry (Scheme 67). Galactosidase-mediated cleavage of the probe would release galactose (562) and the phenol 563 en route to the quinone methide 564, an intermediate with sufficient reactivity to capture a range of nucleophilic residues as adducts (565). Among the enzymes studied were the Xanthomonas manihotis fungal β-galactosidase, which reacted via the arginine residue found within the peptide fragment 56IPRAYWKD;(63)E. coli β-galactosidase, which was decorated at the catalytic glutamic acid residue Glu537; and Bacillus circulans β-galactosidase, which became labeled at Glu259. These results suggested that reactions with this inhibitor were influenced by both its spatial arrangement with respect to the catalytic cavity and the nucleophilicity of the amino acid residue. This methodology could be extended to the characterization of other retaining and inverting glycoside hydrolases.(385)

Figure 13

Figure 13. Design of the fluorescent probe 561 for assessment of galactosidase activity.

Scheme 67

Scheme 67. Mechanism-Based Labeling of a Galactosidase by the Fluorescent Reagent 561
Difluoromethyl substituents of imidazole rings are susceptible to base-catalyzed hydrolytic decomposition, and the rate of fluoride loss rises with increasing pH, consistent with the mechanism depicted in Scheme 68.(386) The half-lives for the conversion of 4-difluoromethylimidazole (566) and 2-difluoromethylimidazole (567) to the corresponding aldehydes 570 and 571 at physiological pH were slightly less than 3 h, largely precluding their application in drug discovery (Scheme 68). In contrast, the calculated half-life of 2-trifluoromethylimidazole (568) at pH 7.4 (corrected for a pKa of 10.11) was approximately 124 days, a result that illustrated the stabilizing effect of an additional fluorine atom on this substituted ring. Difluorohistidinol (569) struck a compromise in stability, with a half-life of approximately 11 h at pH 7.4.(386)

Scheme 68

Scheme 68. Mechanism of Base-Catalyzed Hydrolysis of Difluoromethylimidazoles 566 and 567 to Afford the Corresponding Aldehydes 570 and 571
Trifluoromethyl-substituted aromatic and heterocyclic rings are common motifs in drug design and are typically resistant to base-catalyzed hydrolysis.(1−8) However, an aryl trifluoromethyl moiety that is ortho or para to a hydroxyl or amino substituent can be labile under even mildly basic conditions. A mechanism to explain the hydrolysis of trifluoromethylphenols was elucidated in 1973 during stability studies of the C–F bonds of a number of compounds under weakly basic conditions.(387)o-Trifluoromethylphenol (572), p-trifluoromethylphenol (573), and 4-(3,3,3-trifluoroprop-1-en-1-yl)phenol (574) were hydrolyzed to the corresponding acids 575, 576, and 577 under these conditions. The kinetics of hydrolysis of 572 and 573 were consistent with a mechanism in which the o- and p-phenolates assisted in the displacement of fluoride to give difluoro-substituted quinone methide intermediates (Scheme 69). The stability of m-trifluoromethylphenol against hydroxide treatment substantiated the involvement of the oxyanions of 572 and 573 and argued against the kinetically equivalent direct displacement of fluoride from the neutral species of 572 and 573 by an SN2 process. When the olefin moiety of 574 was reduced, the CF3 group was stable in 1 N NaOH for 24 h, as would be anticipated for the mechanism presented in Scheme 69. These observations suggested the potential to design irreversible enzyme inhibitors in cases where the mode of catalysis would release a phenol derivative.

Scheme 69

Scheme 69. Base-Catalyzed Hydrolysis of Phenol 572 to Give the Acid 575
Drug-related phototoxicity is a potential problem with compounds that absorb ultraviolet light, especially in the range of 290 to 400 nm, and occurs most frequently with compounds that are distributed into the skin or eyes.(388−390) The phototoxicity of a compound is determined experimentally in vivo; however, it may be estimated using key parameters including the maximal molar absorptivity and the energy difference between the lowest unoccupied and highest occupied molecular orbitals. In the case of CF3-substituted aromatic derivatives, absorption of ultraviolet light and electron elevation can lead to degradation and the generation of chemically reactive species.
Aryl CF3 substituents have also been shown to undergo photochemical degradation to acyl fluorides and carboxylic acids. The photochemical degradation of fluphenazine (578), a neuropsychiatric agent, was studied in the presence of peptide-based nucleophiles as part of an effort to understand the source of immune-related side effects that have been observed in therapy.(391,392) Both UVA and UVB light activated 578, with UVA penetration into peripheral capillaries providing an opportunity for photoactivation in vivo. This possibility was enhanced by the long plasma half-life of 578, which ranged from 15 h to several days. Both the triplet and singlet excited states of 578 were long-lived, and a photonucleophilic substitution of fluorine by H2O in the triplet state was proposed as the initial step (Scheme 70). This process afforded the electrophilic acyl fluoride 579, which was hydrolyzed by H2O to give the carboxylic acid (580, Nu = OH). Alternatively, reaction with biological nucleophiles gave rise to acylated adducts (580, Nu = protein).(392)

Scheme 70

Scheme 70. Mechanism of Photodegradation of the CF3 Moiety of 578
The selective serotonin reuptake inhibitor fluoxetine (581) was photoreactive in sunlit surface waters and was degraded in deionized H2O under simulated sunlight (half-life = 55.2 h).(393) The product of this reaction was identified as the carboxylic acid 582, confirming that H2O could act as the ultimate nucleophile in the absence of cellular material (Scheme 71).

Scheme 71

Scheme 71. Photodegradation of 581 under Simulated Sunlight in Deionized H2O to Give the Carboxylic Acid 582
Triflusal (583), a platelet-aggregation inhibitor prodrug used for the prevention and treatment of vascular thromboembolism, is associated with photoallergic side effects.(394) Metabolic deacylation of 583 afforded 2-hydroxy-4-trifluoromethylbenzoic acid (584), the pharmacologically active form, which was subject to hydrolytic photodegradation of the CF3 moiety to give 586 (Scheme 72).(394) The involvement of the triplet state in the photodegradation pathway was shown by laser flash photolysis and quenching experiments, and the binding of a photogenerated derivative of 584 to bovine serum albumin was demonstrated using UV/vis and fluorescence spectroscopy. Amino acids appeared to be the ultimate nucleophiles in this example, reacting with the acyl fluoride 585 to form covalent adducts 587 that were believed to initiate the photoallergic reaction.(394) The role of lysine residues in these reactions was revealed in a study exploring interactions between 585 and ubiquitin, a protein that contains seven Lys residues.(395) In that study, a combination of fluorescence spectroscopy, laser flash photolysis, and proteomic analysis demonstrated the formation of monoadducts 588 as the major products of this reaction. Interestingly, adduction occurred at all of the lysine residues of the protein.

Scheme 72

Scheme 72. Photodegradation of 584, Which Is Produced In Vivo from the Prodrug 583
Similarly, irradiation (310 nm) of 3,5-diamino-1-trifluoromethylbenzene (589) resulted in hydrolytic defluorination to give the carboxylic acid 590, presumably via reaction of an intermediate acyl fluoride with H2O (Scheme 73).(396) However, the presence of the aniline moieties in 589 and its products allowed for competing reactions of the acyl fluoride with the amines to produce dark-colored products including 591, 592, and 593. The progress of this reaction could be monitored by measuring the pH of the solution, which fell from 6.2 to 3.2 as the reaction proceeded.

Scheme 73

Scheme 73. Light-Catalyzed Polymerization of 589
Photoactivation of the CF3 moieties of 4-trifluoromethylphenols to generate latent electrophiles has been explored as a means of targeting lysine residues of proteins.(397) 4-Trifluoromethyl-1-naphthol (594) and 4′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (598) were activated to quinone methide intermediates 595 and 599, respectively, upon irradiation and formed adducts 597 and 601 when photolyzed in the presence of human serum albumin. These reactions were proposed to proceed by way of the imidoyl fluorides 596 and 600 as intermediates (Scheme 74).(397) Additional characterization of these complexes demonstrated chemoselectivity of the electrophilic species toward specific lysine residues within albumin, as 594 reacted covalently with Lys106 and Lys414 located in subdomains IA and IIIA, respectively, and 599 bound to Lys195 in subdomain IIA. Docking and molecular dynamics simulations provided insight into the molecular basis of the selectivity for these subdomains. These studies suggested a broader opportunity to silence target proteins by designing ligands that could be activated with light to covalently modify constituent lysine residues.(397)

Scheme 74

Scheme 74. Use of Aryl CF3 Moieties in the Design of Latent Electrophiles, Which Can Be Generated by Irradiation with Light and Used to Covalently Modify Target Proteins
2-Methyl-1,4-naphthoquinone (menadione, 602) is a subversive substrate of both human and Plasmodium GSH reductases, and the latter is critical to the survival of Plasmodium parasites amid the high concentrations of reactive oxygen species that are present in erythrocytes.(398) Accordingly, these proteins are a validated antimalarial target. Atovaquone (605), which is used in conjunction with the antifolate proguanil, is an inhibitor of the Plasmodium parasite electron transport chain that acts on the mitochondrial cytochrome bc1 complex 3 to interfere with redox cycling and affect the redox equilibrium in infected red blood cells. Because 605 was based on the same naphthoquinone core structure as 602 and lawsone (603), the concept of structural hybridization was explored in an attempt to identify a single compound that could disrupt both functions simultaneously.(398) Trifluoromenadione (604) acted as a prodrug of 603 in which the CF3 moiety was eliminated via a vinylogous haloform-type reaction with two potential underlying mechanisms. In Scheme 75, path a, the Michael addition of H2O to the CF3-substituted carbon atom of 604 set the stage for elimination of CF3 to give 603, the purported mechanism of prodrug activation. The alternative mechanism presented in Scheme 75, path b, envisaged Michael addition of H2O to the more electrophilic carbon atom of the quinone moiety of 604, affording an intermediate enolate that would require tautomerization of the α-hydroxy ketone intermediate to expel CF3 and give 603. The design principle anticipated that 606 would act as a prodrug of 605 in vivo following path a, since path b would be feasible only for R ≠ H.(398) However, 605 did not function as a prodrug of 604, indicating that path b was the likely mode of conversion of 604 to 603.

Scheme 75

Scheme 75. Two Potential Mechanisms for Elimination of CF3 from 604
The 2-methyl-1,4-naphthoquinone derivative 607 and its 2-difluoromethyl analogue 608 were evaluated for inhibition of the water-borne blood fluke Schistosoma mansoni.(399)The methyl-substituted quinone 607 inhibited S. mansoni thioredoxin-GSH reductase (SmTGR), a unique enzyme that protects the pathogen against the reactive oxygen species produced by the host immune response. The inactivation of SmTGR by 607 was time-dependent, forcing the enzyme into a futile cycle that culminated in the buildup of the reduced 3-phenoxymethyl variant 609 and the drawdown of reducing NADPH equivalents that would normally be used to detoxify reactive oxygen species (Scheme 76A). The inhibitory effect of 607 toward SmTGR translated to strong ex vivo antischistosomal activity, demonstrating a proof of concept for the target.(399) However, the inhibitory phenotype of the difluoromethyl analogue 608 toward SmTGR was qualitatively different in that the compound elicited polymerization and precipitation of the enzyme in vitro but failed to kill worms in culture. The different profile was explained by the tautomerization of 608 to the electrophilic o-quinone methide 611, which reacted with the enzyme in the biochemical assay to afford 612 rather than engaging in the redox cycling that would afford 610 (Scheme 76B). The lack of inhibitory activity of 608 ex vivo suggested that only redox-active molecules possessed the desired biochemical pharmacology. However, neither 607 nor 608 was active in vivo, an outcome attributed to poor bioavailability.(399)

Scheme 76

Scheme 76. Substituent at the 2-Position of the Quinone (Methyl or Difluoromethyl) Affects the Chemical and Biochemical Pharmacological Profile of Antischistosomal Compounds
The CF3 moiety of 5-(trifluoromethyl)-2′-deoxyuridine (trifluridine, 613) is a critical determinant of the mechanism-based inhibition of thymidylate synthase that underlies its anticancer action.(400−402)Thymidylate synthase catalyzes the methylation of 2-deoxyuridine monophosphate to give thymidine monophosphate, which as the only intracellular source of this essential DNA building block is critical to support the rapid division and proliferation of immortalized cells. Blocking of thymidylate synthase also leads to the accumulation of uridine monophosphate, increasing the potential for this base to be misincorporated into DNA. The enzymatic methylation catalyzed by thymidylate synthase proceeds via a ternary complex between the substrate uridine monophosphate, thymidylate synthase, and the cofactor 5,10-methylene tetrahydrofolic acid, which is the source of the methyl group installed in thymidine monophosphate. Inhibition of thymidylate synthase by 613 required metabolism to obtain the monophosphate 614, which bound to the active site in the absence of the cofactor and was accepted by the enzyme the same fashion as the natural substrate (Scheme 77). Thus, nucleophilic addition of the catalytic Cys198 to the β-position of the conjugated amide led to an anionic intermediate that was poised to eliminate fluoride from the CF3 moiety, affording the Michael acceptor 615.(402) Addition of the phenol of Tyr146 to the α,β-unsaturated amide 615 followed by elimination of a second fluoride from the adduct generated 616. Although 616 was more stable than 615, it was prone to hydrolytic degradation with ejection of the final fluoride, via 617 and 618, to produce the tyrosine ester 619. The elimination of Cys198 from 619 by a retro-Michael process produced the ester 620. The involvement of Cys198 and Tyr146 in this mechanism was confirmed by treatment of thymidylate synthase with 2′-[3H]-614 followed by proteolytic digestion and sequencing of the labeled peptides. Separately, X-ray crystallographic analysis provided evidence for a covalent bond between the nucleotide and Tyr146 in the enzyme–inhibitor complex. For oncology indications, 613 is typically administered in combination with an inhibitor of thymidine phosphorylase, which prevents the breakdown of 614 to trifluoromethyl thymine.(402)

Scheme 77

Scheme 77. Mechanism of Inhibition of Thymidylate Synthase by 614, the Monophosphate Metabolite of 613
While CF3 substituents can be useful in modulating compound properties, polyfluorination tends to increase the lipophilicity since the π coefficient for fluorine is 0.14.(1−5) Accordingly, each additional CF3 adds 0.42 units to the log P value. However, matched molecular pair analysis has indicated that in the absence of specific effects, up to five fluorine atoms can be installed in a molecule without a significant effect on P-gp-mediated efflux, permeability, lipophilicity, and metabolic stability.(403) Nevertheless, it is important to deploy the CF3 moiety and other lipophilic groups deliberately and with care in order to maintain the lipophilicity within a drug-like range. The cholesteryl ester transfer protein (CETP) inhibitor anacetrapib (621) offered a notable example of how fluorination could be used to obtain a desirable pharmacological profile but concurrently how its overuse could have unintended consequences. There were three CF3 groups present in 621, and these moieties were metabolically inert despite the presence of other soft spots.(404) To date, 621 has been the only CETP inhibitor to successfully complete phase 3 clinical trials, in which it decreased the plasma concentration of low-density lipoprotein, increased the concentration of high density lipoprotein, and reduced cardiovascular events in patients with atherosclerotic disease.(405) However, regulatory filings for 621 were not pursued despite a profile that suggested acceptable efficacy and safety. This decision was due in part to the extraordinarily long terminal pharmacokinetic half-life of 621.(406) In patients who had taken 621 for 18 months, measurable systemic exposure to the drug continued for up to 4 years after the suspension of therapy. Follow-up studies seeking to illuminate this phenomenon revealed extensive distribution of 621 into adipose tissue and lipid droplets in a fashion not dependent on lipase activity or active transport.(407) In retrospect, this behavior is perhaps unsurprising since 621 was characterized by a log D value of 7.1, a high level of lipophilicity that may have helped facilitate interactions with the target protein in the lipoprotein particle. It is instructive to recognize that this pharmacokinetic behavior was not presaged by an especially large steady-state volume of distribution in preclinical species after a single dose (1.1 ± 0.6 L/kg in rats and 0.3 ± 0.1 L/kg in monkeys), perhaps because much of the drug was retained in circulation as the result of an association with plasma proteins (the free fraction was <0.5% in both species). Similarly, a majority of the radioactivity (approximately 80% in rats and 90% in monkeys) was recovered within 48 h after administration of a single oral dose of [14C]-621.(404) This pharmacokinetic profile was consistent with a slow but extensive distribution into adipose tissue, creating a depot from which the drug could escape slowly over a long period of time.(408) Hence, the lipophilicity afforded by CF3 groups should be deployed with care, and the pharmacokinetics of highly lipophilic compounds should be evaluated in multidose studies as a precaution to characterize the extent of accumulation into fatty tissue.

8. Fluorinated Sulfides, Sulfoxides, and Sulfones

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The SCF3 substituent offers unique properties but has not been highly represented in compounds evaluated clinically. The stimulatory amphetamine derivative (±)-tiflorex (flutiorex, 622), the anthelmintic agent monepantel (623), and the coccidiostat toltrazuril (624) are examples of fluorinated sulfides that have been studied clinically, while the dihydroorotate dehydrogenase inhibitor 625 has been examined in a preclinical setting. The SCF3 substituent is lipophilic (π = 1.44(254,320)), contributing to the distribution of SCF3-substituted compounds into fatty tissue. This pattern was apparent during a small clinical trial of 622 that explored its potential as an anorectic agent.(409,410) This study found that the concentration of 622 in erythrocytes was 4-to-8-fold higher than that in plasma over a time course of 6 h. Moreover, urinary elimination of 622 remained measurable at 48 h postadministration, suggesting low clearance and/or extensive distribution. This finding was despite the observation that urinary excretion of unchanged 622 over 24 h represented only a small fraction of the dose administered.(409,410)
The CF3S moiety is susceptible to oxidative metabolism to afford both the sulfoxide and the sulfone, metabolites that have been observed with 622625. Oxidation to the sulfoxide may be characterized by a degree of enantioselectivity depending on the substrate and the enzyme involved, which is typically either a member of the P450 superfamily or an FMO. For example, biotransformation studies of 624 in RLM revealed that the relative rates of sulfoxidation to give the enantiomers 626 and 627 (the absolute configurations of these two sulfoxides are not known) could be manipulated by pretreating rats with different inducing agents prior to the harvesting of microsomes (Scheme 78).(411) Since the P450 enzymes induced by these agents were known, it was possible to identify certain inducible enzymes that catalyzed the formation of 626 (CYP1A1/CYP1A2) and others that favored the opposite enantiomer 627 (CYP2B1/CYP2B2). Consistent with this finding, pretreatment of rats with 3-methylcholanthrene, an inducer of CYP1A, prior to administration of 624 led to dramatic changes in the plasma AUCs of the sulfoxide enantiomers. Specifically, the AUC of 626 increased by approximately 3-fold, whereas the AUC of 627 declined to only 14% of the value in the vehicle control.(412) The second step in this metabolic sequence, oxidation of the sulfoxide enantiomers 626 and 627 to the achiral sulfone 628, was also stereoselective (Scheme 78). Although both of these reactions were catalyzed by CYP3A, the rate of oxidation was 7-fold higher for 626. Hence, the exposure of each discrete sulfoxide enantiomer was a composite function of the rate and enantioselectivity of the reactions governing its formation and clearance, both of which were oxidative processes.

Scheme 78

Scheme 78. Oxidative Metabolism of the CF3S Substituent of 624 in RLM and Rats to Afford the Sulfoxides 626 and 627 and Sulfone 628a

aThe absolute configurations of the sulfoxides 626 and 627 were not determined, and the assignments shown are arbitrary.

Oxidative metabolism typically facilitates the disposition of drugs, rendering products that are more hydrophilic and more susceptible to transfer into bile and urine. However, the metabolic sequence described above tends to result in the formation of sulfone metabolites that exhibit longer half-lives in vivo than the parent sulfides. For example, the plasma half-life of 622 following intravenous administration to anesthetized rats was 7.4 h, but the half-lives of the sulfone derived from 622 and its N-dealkyated metabolite were 2.6 and 9.3 h, respectively.(413) Remarkably, the plasma AUC of the sulfone derived from 622 in this experiment was approximately 12-fold higher than the AUC of the sulfide 622. Analogous trends were noticed in a series of β-hydroxy enamides, in which a comparison of a CF3S-substituted compound to its CF3SO2 metabolite revealed the latter to have a 7-fold longer half-life in the rat.(234) The anthelmintic drug 623 was also converted to a biologically active sulfone metabolite exhibiting a larger steady-state volume of distribution, lower clearance, and increased mean residence time compared with 623.(414) Similarly, the half-life of 628 was longer than that of 624 in pigs (Scheme 78).(415) The common theme in these examples is that although oxidation of the CF3S moiety to the sulfone increases its hydrophilicity (the π coefficient for the CF3SO2 moiety is 0.55 compared with 1.44 for CF3S, and both are more lipophilic than CH3SO2, for which π = −1.63), these metabolites retain significant lipophilicity that renders them prone to tissue penetration.(320) These properties may imbue the sulfone with reduced clearance and/or increased distribution relative to the sulfide, both of which would work to lengthen the half-life in vivo. Thus, it should be anticipated that a CF3S substituent will be susceptible to metabolism to the sulfoxide and sulfone derivatives in vivo and that those metabolites may represent the main drug-related compounds circulating in the blood. However, it should be emphasized that CF3S substituents may not necessarily confer reduced metabolic stability relative to CF3O. This trend was exemplified by 630 and 632, the homologues of pretomanid (629) and riluzole (631), respectively, in which the CF3O moieties were replaced by CF3S.(416) As captured in Table 7, 630 and 632 were characterized by rates of metabolic clearance in HLM that were similar to those of their respective CF3O-substituted homologues 629 and 631. These SCF3-substituted compounds also exhibited higher lipophilicity (log P) and lower aqueous solubility (pH 6.8) than their matched OCF3-substitued pairs, whereas no consistent trend was apparent with respect to plasma protein binding or membrane permeability.
Table 7. In Vitro Profiling Data for 629 and 631 and Their Respective CF3S Analogues 630 and 632
compoundlog Paqueous solubility at pH 6.8 (mM)MDCK LE Papp A-BaClint (μL min–1 mg–1)bhuman plasma protein binding
6292.20.00821.1<2538%
6302.70.00515.5<2560%
6313.20.986118.338.985%
6323.60.124152.040.976%
a

Passive permeability in Madin–Darby canine kidney low-efflux cells, expressed as a ratio of concentrations.

b

Intrinsic clearance in HLM.

A similar sequence of metabolic reactions can be expected in connection with the use of α,α-difluoroethyl sulfides (CH3CF2S), which are also converted sequentially to sulfoxides and sulfones in a stereoselective manner.(253) These compounds are characterized by lower lipophilicity than the corresponding CF3S derivatives, a function of the dipole moment associated with the CF2 element, and therefore offer a potentially useful alternative in drug design.
The strongly electron-withdrawing aryl substituents CF3SO and CF3SO2 may confer unique properties to a molecule, projecting influence over metabolic pathways that introduce changes distal to the substituent. This concept was illustrated nicely by a study of substituent effects on the reactivity of 633, suicide inhibitors of phospholipase A2.(417) These inhibitors shared structural similarities with the native substrate of the enzyme and were hydrolyzed by phospholipase A2 to release the phospholipid portion of the molecule and the carboxylic acid 634 (Scheme 79). The chemical stability of 634 was directly related to the electron-withdrawing character of the R substituent, with strong electron-withdrawing groups like CF3SO2 stabilizing the negative charge on the phenolate of 635 and facilitating the formation of the reactive cyclic gem-dimethylglutaric anhydride 636. The rate of the cyclization step determined the extent of mechanism-based inhibition of phospholipase A2, with those substrates that cyclized slowly allowing diffusion of 634 away from the enzyme prior to release of the anhydride, resulting in nonspecific acylation.(417) However, rapid formation of the anhydride occurred mostly within the active site, increasing the chance of reaction with the enzyme. Consistent with this model, the empirical rate of enzyme inactivation (k) in this experiment was modeled with reasonable accuracy by the Hammett equation, log(k/k0) = σpρ, using σp constants measured previously for each of the phenyl substituents that were investigated. This inactivation rate increased as a function of the R group (CN < CH3SO2 < CF3SO < NO2 < CF3SO2), correlating approximately with the σp values, and the ρ value of 2.4 measured experimentally suggested a strong dependence on substituent effects. This example is a reminder that oxidative metabolism of an aryl SCF3 group may result in changes that strongly influence the electronics of the aryl ring and in extreme cases may lead to overall increases in chemical reactivity.

Scheme 79

Scheme 79. Substituent Effects on Phospholipase A2 Suicide Inhibition by 633
Although the COSCH2F motif is not used widely in medicinal chemistry, the glucocorticoid agonist fluticasone furoate (145) offers a visible example of the use of this moiety as a soft spot for oxidative metabolism.(13,161,418) Clinical administration of 145, a popular treatment for locally defined inflammatory disorders, is by inhalation for the treatment of asthma or by topical application for dermal indications. While 145 had a relatively long half-life of 15.3 h, driven in part by distribution into tissue (Vd = 642 L), extensive first-pass hepatic extraction limited the oral bioavailability to just 1.6%. Specifically, the rapid metabolism of 145 to the corresponding 17β-carboxylic acid 638, which was inactive as a glucocorticoid agonist, restricted the exposure of the compound in vivo and minimized the potential for systemic side effects (Scheme 80).(161) Studies using HLM demonstrated that the formation of 638 was inhibited by ketoconazole, an inhibitor of CYP3A, but not by selective chemical inhibitors of other P450 enzymes. Similarly, experiments using recombinant enzymes implicated CYP3A in metabolic turnover.(418) Collectively, these results framed the COSCH2F group as a limiting factor in the systemic exposure of 145 in humans. This molecule in essence acts as a soft drug, a salient point for those looking to revisit this feature in the design of medicines to be administered orally.(13)

Scheme 80

Scheme 80. Metabolism of the [(Fluoromethyl)thio]carbonyl Moiety of 145 by P450 to Afford the Carboxylic Acid 638
The pentafluorosulfanyl (SF5) substituent continues to attract the attention of the medicinal chemistry community, although there are few (if any) examples of applications that take full advantage of its unique properties.(419,420) In a study comparing the potential of several substituents to act as replacements for the tert-butyl moiety, the SF5 substituent conferred the highest aqueous solubility and lowest pKa among the homologues tested in addition to a log D value between those of tert-butyl and CF3. These results echoed a longstanding characterization of SF5 as being both highly polar and highly lipophilic.(421) Against this backdrop, several studies have examined substitution of CF3 by SF5 in a range of structural backgrounds in an attempt to improve on the composite properties of the CF3 derivatives.(422−425) The dihydroorotate dehydrogenase inhibitor DSM265 (639), an antimalarial agent, is the only compound bearing a SF5 substituent that has been advanced into clinical development.(426,427) Since malaria tends to afflict rural areas where access to health clinics may limit the delivery and quality of care, a medicine that can be administered easily and infrequently is highly advantageous. Compound 639 shows promise in this regard, exhibiting a long duration of action that may allow the drug to be administered as a single dose. It achieved an extended duration with a long pharmacokinetic half-life (86 to 118 h in humans) that was driven by low metabolic clearance, extensive distribution into tissue, and extensive binding to plasma proteins.(427) These characteristics clearly reflected the lipophilicity and metabolic stability of the SF5 substituent. Of the biotransformation pathways of 639 that have been characterized, none appeared to affect the SF5 moiety directly. It is also important to note that the preclinical studies of 639 revealed few inherent liabilities that might extend to other compounds with SF5 substituents.(426) Specifically, 639 did not induce P450, demonstrated little off-target activity in a broad pharmacology screen (ion channels, kinases, etc.), and exhibited marginal activity in patch-clamp studies that was offset by its low free fraction. Furthermore, preclinical safety studies showed that high doses of 639 were tolerated across preclinical species and that neither 639 nor the embedded aniline (4-pentafluoro-λ6-sulfanylaniline) gave rise to revertants in the Ames mutagenicity assay. With respect to issues to be resolved in the development of 639, one of the main challenges relates to its pharmaceutics properties and the apparent need for an enabled formulation. For the first-in-human study, 639 was formulated as a spray-dried dispersion that required suspension in a vehicle on-site, a process that was deemed to be cumbersome.(427) Hence, more work along these lines is indicated to identify a viable solid dosage form or other formulation suitable for use in remote areas.

Conclusion

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The ever-deepening understanding of the unique attributes of fluorine, coupled with the development of synthetic methodologies that are expanding access to new and useful fluorinated motifs, has led to the extensive deployment of this element in drug design. The judicious use of fluorine in a molecule can affect the physical, biochemical, pharmacological, and pharmacokinetic properties in ways that can be beneficial. The high strength and large dipole moment of the C–F bond, along with the strong electronegativity, small size, and modest lipophilicity of fluorine all subtend a versatility in drug design that is unmatched by any other element. However, while fluorine has often been used to enhance metabolic stability, studies of fluorinated compounds have uncovered metabolic pathways in which the fluorine atom influences the metabolic fate, informing the need to exercise care in its deployment. Despite its strength, there are many examples of C–F bond rupture during metabolism. This aspect of fluorine chemistry has been recognized for some time and specifically exploited in the design of enzyme inhibitors. However, other motifs are emerging that can be problematic in a more cryptic sense. The biotransformation of fluorinated compounds can set the stage for the departure of fluoride as a leaving group, sometimes generating chemically reactive intermediates. There are several other examples in which fluorinated molecules are subject to multistep metabolic pathways, resulting in the release of low-molecular-weight fluorinated toxins like 2-fluoroethanol, fluoroacetaldehyde, fluoroacetic acid, and fluorolactic acid. While fluorine is only modestly more lipophilic than a hydrogen atom, its use as part of a CF3 or SF5 moiety adds significantly to the lipophilicity of a compound. It has been suggested that up to five fluorine atoms can be installed as hydrogen atom replacements with minimal impact, but more heavily fluorinated compounds may present challenges with respect to drug distribution and disposition if global lipophilicity is not controlled. Nevertheless, the attributes of fluorine are such that its prominence in drug design will continue to grow. A collective view of the emerging data on the metabolism and disposition of fluorinated compounds suggests that some care should be exercised in its deployment in drug candidates.

Author Information

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  • Corresponding Author
  • Authors
    • Yue-Zhong Shu - Pharmaceutical Candidate Optimization, Bristol Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States
    • Xiaoliang Zhuo - Pharmaceutical Candidate Optimization, Bristol Myers Squibb Company, 100 Binney Street, Cambridge, Massachusetts 02142, United States
    • Nicholas A. Meanwell - Discovery Chemistry Platforms, Small Molecule Drug Discovery, Bristol Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543, United StatesOrcidhttp://orcid.org/0000-0002-8857-1515
  • Notes
    The authors declare the following competing financial interest(s): All of the authors are employees and shareholders of Bristol Myers Squibb.

Biographies

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Benjamin M. Johnson

Benjamin M. Johnson received his Ph.D. from the University of Illinois at Chicago, where he learned to use liquid chromatography–tandem mass spectrometry in the study of natural products. Since 2004 he has been at Bristol Myers Squibb (BMS), where he oversees an analytical drug-metabolism laboratory and leads project teams working to discover medicines for cancer and autoimmune disorders. He was involved in the discovery of daclatasvir (the first-in-class HCV NS5A inhibitor), rimegepant and vazegepant (calcitonin-gene-related peptide receptor antagonists), GSK-3532795/BMS-955176 (an HIV-1 maturation inhibitor), and LX9211 (an adaptor associated protein kinase 1 inhibitor) in addition to other compounds in clinical development. After hours, he is an avid runner and home cook.

Yue-Zhong Shu

Yue-Zhong Shu received his Ph.D. from the University of Toyama in Japan and conducted his Ph.D. and postdoctoral studies at Virginia Polytechnic Institute and State University in natural product chemistry and biotransformation. He joined BMS in 1992, where he became the leader of the natural product chemistry group. Over the past 20 years, he has led biotransformation teams supporting drug discovery in the fields of virology, neuroscience, metabolic diseases, oncology, immunology, cardiovascular disease, and fibrosis. His expertise in drug metabolism spans a range of synthetic molecules and nontraditional modalities, including antibody–drug conjugates, macrocyclic peptides, and protein degradation agents. He has been involved with many BMS drug candidates advanced to clinical development and to the marketplace.

Xiaoliang Zhuo

Xiaoliang Zhuo received his Ph.D. in toxicology from State University of New York at Albany and performed postdoctoral research at the University of Pennsylvania before joining BMS in 2004. He supports discovery research and clinical development across therapeutic areas, with a focus on the characterization and optimization of ADMET properties. These efforts have helped to advance several molecules with optimized profiles to clinical evaluation, including the HCV NS5B inhibitor beclabuvir. Since becoming a Diplomate of the American Board of Toxicology in 2014, he has investigated mechanisms of liver injury induced by clinical candidates and developed strategies to assess and mitigate the off-target risk. He enjoys writing research articles and has published papers on novel biotransformation pathways.

Nicholas A. Meanwell

Nicholas A. Meanwell received his Ph.D. from the University of Sheffield and conducted postdoctoral studies at Wayne State University before joining BMS in 1982. He has been associated with the discovery of BMY-433771, an inhibitor of respiratory syncytial virus fusion, the HIV-1 attachment inhibitor temsavir/fostemsavir, the HIV-1 maturation inhibitor GSK-3532795/BMS-955176, and the marketed HCV inhibitors asunaprevir (NS3), daclatasvir (NS5A), and beclabuvir (NS5B). He is the corecipient of a 2014 PhRMA Research and Hope Award for Biopharmaceutical Industry Research and a 2017 ACS Heroes of Chemistry Award. He was the recipient of the 2015 Philip S. Portoghese Medicinal Chemistry Lectureship Award and was inducted into the ACS Division of Medicinal Chemistry Hall of Fame in 2015.

Abbreviations Used
ADH

aldehyde dehydrogenase

ALDH

alcohol dehydrogenase

CB

cannabinoid receptor

CETP

cholesteryl ester transfer protein

CFC

chlorofluorocarbon

CRF

corticotropin-releasing factor

CNS

central nervous system

DAAO

d-amino acid oxidase

DDAH

dimethylarginine dimethylaminohydrolase

ddI

2,3-dideoxyinosine

ddP

2,3-dideoxypurine

DPP4

dipeptidyl peptidase-4

FMO

flavin-containing monooxygenase

GABA

γ-aminobutyric acid

GABAAT

γ-aminobutyric acid aminotransferase

GSH

glutathione

GST

glutathione S-transferase

GSTZ

glutathione S-transferase zeta

HCFC

hydrochlorofluorocarbon

HCV

hepatitis C virus

HFC

hydrofluorocarbon

HLM

human liver microsomes

ip

intraperitoneal

iv

intravenous

KSP

kinesin spindle protein

LC

liquid chromatography

MAO

monoamine oxidase

MBI

mechanism-based inhibitor

MDR

multidrug resistance protein 1

MS

mass spectrometry

NAD

nicotinamide adenine dinucleotide

PDE

phosphodiesterase

PET

positron emission tomography

P-gp

P-glycoprotein

PLP

pyridoxal 5′-phosphate

RLM

rat liver microsomes

SAHase

S-adenosyl-l-homocysteine hydrolase

SM

squalene monooxygenase

SmTGR

thioredoxin-glutathione reductase

SSAO

semicarbazide-sensitive amine oxidase

SULT

sulfotransferase

TDI

time-dependent inhibition

UDPGA

uridine diphosphate glucuronic acid

UGT

UDP-glucuronosyltransferase

VAP-1

vascular adhesion protein-1

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  • Abstract

    Figure 1

    Figure 1. Fluorine-containing drugs approved by the U.S. Food and Drug Administration through the end of 2019.

    Scheme 1

    Scheme 1. (S)-γ-Fluoroleucine (1) Converts Spontaneously to Amino Lactone 2 with Loss of HF

    Figure 2

    Figure 2. Fluoroacetic acid (5) and known metabolic precursors 612.

    Scheme 2

    Scheme 2. Biosynthesis of 5 and 18 and (Inset) Details of the Transition State as Proposed by Theoretical, Structural, and Kinetic Studies

    Scheme 3

    Scheme 3. Biochemical Reactions of Native and Fluorinated Substrates Catalyzed by Aconitasea

    a(A) Dehydration of citric acid (19) to form 20 is followed by rehydration to give isocitric acid (21). (B) Compound 5 is converted to fluoroacetyl-CoA (22), which reacts by a Claisen condensation with 23 to give (−)-erythro-(2R,3R)-2-fluorocitric acid (24) in a stereospecific manner. Dehydration of 24 to give 25 is followed by a flip in the active site as a prelude to the addition of H2O. This addition produces 4-hydroxy-trans-aconitate (26), a potent and tight-binding inhibitor of aconitase that represents the ultimate toxicant produced by the biochemical transformation of 5.

    Scheme 4

    Scheme 4. Metabolism of (+)-erythro-(2S,3S)-2-Fluorocitric Acid (27) by Aconitasea

    a(+)-erythro-(2S,3S)-2-Fluorocitric acid (27) is subject to elimination of H2O to afford 28, which flips in the enzyme active site to set the stage for the addition of H2O to produce 29. This compound collapses with loss of HF to give oxalosuccinic acid (30), which decarboxylates to afford α-ketoglutaric acid (31).

    Scheme 5

    Scheme 5. Potential Mechanism for the Metabolic Activation of 1,3-Difluoro-2-propanol (32) to Form Fluoroacetic Acid CoA Estera

    aThis process is hypothesized to proceed via oxidation of 32 by ALDH to give 1,3-difluoroacetone (33) followed by a Baeyer–Villiger-type process to generate ester 12′. This ester would be anticipated to convert readily to 5 by hydrolysis or otherwise undergo esterase-mediated cleavage to release 5, formaldehyde, and fluoride.

    Figure 3

    Figure 3. Example of the tactical deployment of fluorine to modulate the basicity in piperidine-based KSP inhibitors.

    Scheme 6

    Scheme 6. Major Metabolic Pathway for 35 in RLM and Hepatocytes

    Scheme 7

    Scheme 7. Enzymatic Baeyer–Villiger Oxidation of Z-Phe-Ala-CH2F (40)

    Scheme 8

    Scheme 8. Covalent Inhibition of ATG4B by the Fluorinated Peptide Mimetic 45 to Afford Alkylated Enzyme 46

    Scheme 9

    Scheme 9. Biotransformation of 49a

    a(a) 5-Fluorouracil (49) is a substrate of both orotate phosphoribosyl transferase, which catalyzes the addition of a phosphorylated ribose moiety to yield 55, and dihydropyrimidine dehydrogenase, which carries out the initial step in the catabolic pathway that mediates the disposition of the drug. (b) The triphosphate metabolite 56 may be incorporated into DNA, leading to downstream single-strand breaks. (c) The monophosphate 57 reacts with thymidylate synthase and 5,10-methylene tetrahydrofolate, forming the covalent inactivated enzyme complex 58. (d) The multistep catabolic sequence proceeds through a postulated carbon–carbon bond cleavage and decarboxylation, culminating in the formation of 5, in which the acid group may be derived from either C-4 or C-6 of the starting material.

    Scheme 10

    Scheme 10. Metabolism of Capecitabine (59) to 49

    Figure 4

    Figure 4. Optimization of HCV NS4B inhibitors to avoid the production of 33, a metabolic precursor to 5.

    Scheme 11

    Scheme 11. Compounds Containing N-Trifluoroethyl Groups May Be Metabolized In Vivo to Release 71, Which Causes Testicular Toxicity

    Scheme 12

    Scheme 12. Mechanism of Defluorination of 5 by Mammalian and Bacterial Defluorinase Enzymes

    Scheme 13

    Scheme 13. Metabolic Pathways of 5, 10, and 11 in Rodents

    Scheme 14

    Scheme 14. Metabolic Pathways of HCFCs 8385a

    aThe metabolism of 8385 proceeds in each case through an aldehyde intermediate, which is subject to differential metabolism depending on the pattern of halogen substitution (X′, X″, and X‴).

    Scheme 15

    Scheme 15. Metabolism of HFC-245fa (86)

    Scheme 16

    Scheme 16. Metabolic Activation of 94, Which is Metabolized by P450 along (a) Reductive and (b) Oxidative Pathwaysa

    a(a) The reductive pathway involves a one-electron reduction with loss of bromine to afford a radical, which either abstracts a hydrogen atom prior to exhalation or is further reduced. The product of reduction is an unstable 1-chloro-2,2,2-trifluoroethyl carbanion intermediate that eliminates fluoride to give 96, which is also exhaled. (b) The oxidative pathway involves oxidation and loss of HBr to give 97, which is readily hydrolyzed to give 67.

    Scheme 17

    Scheme 17. Metabolism of 98

    Scheme 18

    Scheme 18. Metabolism of 104, a Base-Catalyzed Degradation Product of 98, in Rats and Humans

    Scheme 19

    Scheme 19. In Vitro Metabolism of a Homologous Series of [18F]fluoroalkylbiphenyl Derivativesa

    aBenzylic oxidation of 114 releases fluoride immediately, whereas 117 and 121 require successive benzylic oxidations via the intermediate alcohols 118 and 122, respectively, to afford the ketones 119 and 123. Since the release of fluoride is faster from the intermediate derived from 121 than that from 117, the latter is deemed to have the best overall properties. This compound is oxidized in successive steps to 118 and the α-fluoro ketone 119, which is believed to undergo spontaneous but slow α-elimination (16% over 1 h) to give the corresponding enol. This enol is tautomeric with the ketone 120.

    Figure 5

    Figure 5. 11β-Fluoroalkyl and 11β-fluoroalkoxy estrogen derivatives explored for their potential as PET imaging agents.

    Figure 6

    Figure 6. Structures of 11C-WAY-100635 (11C-129) and [18F]-derived analogues 130135 explored as potential PET tracers. The asterisk denotes the position of the 11C label in 11C-129.

    Scheme 20

    Scheme 20. Metabolism of ((1R,2S,3R)-2,3-Difluorocyclohexyl)benzene (136) by C. elegansa

    aComplete conversion was obtained over 72 h at 28 °C. Compounds 137139 represent the metabolites observed in the study, which included other polyfluorinated substrates in addition to 136. The main site of oxidation was at the benzyic carbon rather than at sites substituted by fluorine. The unexpected formation of 140 was not explained but serves as a reminder that fluorinated alkyl groups may not always be metabolically inert.

    Figure 7

    Figure 7. Influence of the pattern of difluorination on the physicochemical properties of the matched pair of indoles 141 and 142 and the HIF2α inhibitors 143 (PT2385) and 144 (PT2977). The solubilities of 141 and 142 were measured in aqueous buffer (pH 6.5), while clearance was measured in human liver microsomes and protein binding of 143 and 144 was measured in human plasma.

    Scheme 21

    Scheme 21. Fluticasone Furoate (145) and Flunisolide (146) Are Both Metabolized by Allylic Oxidation at C-6, Which Results in the Loss of Fluorinea

    a(A) Fluticasone furoate (145) undergoes abstraction of the axial 6-hydrogen by P450 with rebound oxidation, leading to 147. This intermediate eliminates fluoride to form the keto compound 148, which is reduced to the 6-hydroxy metabolite 149. While the configuration of 149 has not been determined, analogy to flunisolide (146), which is metabolized in a stereospecific manner (B), would suggest that both steroids likely undergo β-oxidation at this site.

    Figure 8

    Figure 8. Fluorinated alkenes can serve as isosteres of a ketone, ester, or amide (A) or a carbonyl moiety (B), depending on the specific structural arrangement.

    Scheme 22

    Scheme 22. Proposed Nucleophilic Substitution of 1,1,3,3,3-Pentafluoro-2-(trifluoromethyl)prop-1-ene (158) with Nucleophiles

    Figure 9

    Figure 9. Correlation among the reactivity of perfluorinated olefins, the stability of carbanion intermediates, and lethality.

    Scheme 23

    Scheme 23. Metabolic Activation of 160 by CYP2E1 to Generate Fluoroethylene Oxide (166), a Reactive Intermediate That Can Modify DNA Bases or Form Downstream Products

    Scheme 24

    Scheme 24. Proposed Metabolic Pathway of 157 Leading to Tissue-Selective Toxicitya

    aThe reaction of 157 with hepatic GSH generates S-(1,1,2,2-tetrafluoroethyl)GS (174), which is processed to S-(1,1,2,2-tetrafluoroethyl)-l-cysteine (175) and excreted into bile. Following absorption, 175 undergoes β-lysis to form the thiolate intermediate 176 along with pyruvic acid and ammonia. Elimination of fluoride from 176 generates the reactive thionoacyl fluoride 177, which is hypothesized to be the ultimate toxicant.

    Scheme 25

    Scheme 25. Metabolism of 2-Bromo-2-chloro-1,1-difluoroethylene (182)

    Scheme 26

    Scheme 26. Conversion of Squalene (192) to (3S)-2,3-Oxidosqualene (193) by Squalene Monooxygenase, the Initial Step in the Biosynthesis of Sterols

    Scheme 27

    Scheme 27. Proposed Mechanisms of Inhibition of SAHase by Neoplanocin A (201) and Fluoroneplanocin A (202)

    Scheme 28

    Scheme 28. Inhibition of MAO B by Mofegiline (209)a

    aThe inhibition results from oxidation of the primary amine to the conjugated iminium 210, a Michael acceptor that reacts with N5 of the flavin coenzyme, forming the covalent adduct 211. Loss of fluoride from 211 results in the formation of a covalent complex (212).

    Scheme 29

    Scheme 29. Inactivation of SSAO/VAP-1 by Mofegiline (209)a

    aMofegiline is believed to condense with (2,4,5-trihydroxyphenyl)alanine quinone (214), the SSAO/VAP-1 cofactor, to form the quinone imine 215. Tautomerization of 215 affords the conjugated imine 216, which is intercepted by a proximal nucleophilic amino acid residue to give 217. This intermediate can eliminate fluoride, leading to the irreversibly inactivated enzyme 218.

    Scheme 30

    Scheme 30. Metabolic Pathways of Mofegiline (209) in Dogs and Humans

    Scheme 31

    Scheme 31. Proposed Mechanism for the Formation of 222 from 209 via Carbamic Acid 221

    Scheme 32

    Scheme 32. Proposed Mechanism for the Formation of 220 from 209

    Scheme 33

    Scheme 33. Proposed Mechanism of Irreversible (Path a) and Reversible (Path b) Inhibition of GABAAT by the GABA Mimic Vigabatrin (229)

    Scheme 34

    Scheme 34. Proposed Mechanism of Irreversible Inhibition of GABAAT by 228a

    aThe inhibition is initiated by formation of the Schiff base 234 with PLP (a). Arg192 engages the carboxylate moiety to anchor the inhibitor in the active site of the enzyme. Tautomerization (b) of 234 generates the Michael acceptor 236, which is subject to successive hydrolytic reactions (c and d) that liberate 2 equiv of fluoride to ultimately produce 238. Because of conformational restrictions, 236 reacts with H2O rather than the catalytic Lys329 to form an unstable difluorohydrin, which degrades to the acyl fluoride 237 and then to PLP-bound diacid 238. The nascent carboxylate in 238 is positioned to engage in a second electrostatic interaction with Arg445. Hydrolysis of 238 (e) releases PLP-derived amine 239 and (1S)-4-oxocyclopentane-1,3-dicarboxylate (240), which can spontaneously undergo decarboxylation (f) to give (S)-3-oxocyclopentane-1-carboxylate (241).

    Scheme 35

    Scheme 35. Proposed Mechanism of the Metabolism of OSI-930 (242)a

    aOSI-930 (242) undergoes single-electron oxidation by P450, creating a radical intermediate that exists in both nitrogen- and carbon-centered resonance forms (243) prior to recombination/rebound hydroxylation. The resulting hemiketal 244 loses CF3OH, which rapidly degrades to fluorophosgene (246) at room temperature, producing the transient quinone imine intermediate 245. Quinone 245 is then reduced to the observed hydroxyphenyl metabolite 247.

    Scheme 36

    Scheme 36. Proposed Metabolic Pathways to Explain the Formation of Metabolites Observed with the CRF Receptor Antagonist BMS-665053 (255)

    Scheme 37

    Scheme 37. Displacement of the OCHF2 Group in 263 by a Biological Thiol

    Scheme 38

    Scheme 38. Metabolism of 271 by C. elegans, Which Catalyzes O-Demethylation of the Anisole Methyl Moiety to Afford the Hydrolytically Sensitive Product 272

    Scheme 39

    Scheme 39. Two Potential Mechanisms by Which Lumacaftor (286) May Be Metabolized to the Catechol 290a

    a(A) Arene oxidation of 286 by P450 affords 287, which degrades via 288. The degradation pathway for 288 could occur by the direct departure of the phenolate with concomitant release of fluorophosgene (246) or via elimination of HF and hydrolysis of the carbonofluoridate product followed by decarboxylation. Collapse to o-quinone 289 is followed by reduction to the catechol 290, which is either excreted or sulfated. (B) Arene oxidation of 286 at an alternate site would afford epoxide intermediate 291, which could degrade hydrolytically to give 292. Rearrangement of this intermediate with loss of H2O and reduction by an overall mechanism analogous to that described above would afford catechol 290 via the o-quinone 289.

    Scheme 40

    Scheme 40. Mechanism-Based Glycosidase Inactivation by the Glycoside 293 Exhibiting a Difluorinated Ethera

    aThe substituted ether of the glycoside is displaced (294), generating 295 and the difluorinated alcohol 296, which decays quickly to the acyl fluoride 297. The acyl fluoride then reacts covalently with an amino acid residue in the active site, inactivating the enzyme (298), or diffuses away from the enzyme and is either hydrolyzed or captured by an adventitious nucleophile such as a protein.

    Scheme 41

    Scheme 41. Metabolic Pathway Elucidated for the DPP4 Inhibitors 302 and 303 in RLM

    Scheme 42

    Scheme 42. Alternative Epoxide-Based Metabolic Pathway Contemplated for the DPP4 Inhibitors 302 and 303 in RLM

    Figure 10

    Figure 10. Relationships between structure and CYP3A inhibition for a series of azepane derivatives.

    Scheme 43

    Scheme 43. Potential Metabolic Pathways Giving Rise to CYP3A TDI from Difluorinated Azepane Derivativesa

    aProposed metabolic pathways that may result in TDI of P450 by 318: (a) Oxidation of the primary amine in two steps yields the nitroso derivative 326, which coordinates to the heme protein. (b) Oxidative deamination yields the ketone 327, which undergoes elimination to give the α,β-unsaturated carbonyl 328 and then nucleophilic attack by a biological thiol to give 329 and 330. (c) In the des-NH2 series, α-hydroxylation of the azepane ring to give 331 leads to conjugated imine 332 and then 333, which also undergoes nucleophilic attack to give 334.

    Scheme 44

    Scheme 44. Mechanism of Inhibition of Bacterial Alanine Racemase by d-Fluoroalanine (339)

    Scheme 45

    Scheme 45. Mechanism of Inhibition of Bacterial Alanine Racemase by Difluoroalanine (341)

    Scheme 46

    Scheme 46. Mechanism of Inhibition of Bacterial Alanine Racemase by Trifluoroalanine (342)

    Scheme 47

    Scheme 47. Mechanism of Inhibition of Bacterial Alanine Racemase by Fluorovinylglycine (365)

    Scheme 48

    Scheme 48. Mode of Inhibition of Amino Acid Decarboxylases by β-Fluorinated Amino Acid Derivatives 386

    Scheme 49

    Scheme 49. Mode of Inhibition of Tryptophan Synthase by 394

    Scheme 50

    Scheme 50. (a) E1cb Mechanism of HF Elimination from (R)-404; (b) E2 Mechanism of HF Elimination from (S)-404

    Figure 11

    Figure 11. Conformations of (a) (R)-404 and (c) (S)-404 recognized initially by GABAAT and (b, c) the two low-energy conformations of (S)-404.

    Scheme 51

    Scheme 51. Proposed Mechanism of Defluorination of 410 by GABAAT and Further Metabolism to Give 416 and 417

    Scheme 52

    Scheme 52. Metabolic Fate of 340

    Scheme 53

    Scheme 53. Pyruvate Dehydrogenase Uses the Cofactor Thiamine Diphosphate (419) to Effect the Decarboxylative Degradation of 355

    Scheme 54

    Scheme 54. Proposed Bioactivation of 430 to Give Electrophile 432 and Trapping by a Lys of Serum Albumin

    Scheme 55

    Scheme 55. Aromatic Oxidation Accompanied by the NIH Shift of Fluorine in Fluorobenzenes

    Scheme 56

    Scheme 56. Metabolism of 448, a Quinoxaline-Based Non-Nucleoside Inhibitor of HIV-1 Reverse Transcriptase

    Scheme 57

    Scheme 57. Potential Metabolic Activation Pathways of the Hedgehog Pathway Inhibitor 452

    Scheme 58

    Scheme 58. Proposed Mode of Inhibition of HCV NS5B Polymerase by 456 in HCV Replicons

    Scheme 59

    Scheme 59. Proposed Bioactivation Pathway for the BACE-1 Inhibitor 464, a 5-Fluorinated Pyrimidine Derivative Associated with CYP3A4 TDI

    Scheme 60

    Scheme 60. Proposed Metabolic Pathways of the Pentafluorophenyl-Based DPP4 Inhibitor 470 to give 471 and 472 (the Regiochemistry of GSH in 471 and 472 Was Not Determined)

    Scheme 61

    Scheme 61. Formation of N-Oxide Metabolites 501 and 502 from 500 In Vivo

    Figure 12

    Figure 12. Metabolic soft spots associated with 488 in liver microsomes.

    Scheme 62

    Scheme 62. Mechanism Proposed to Explain the Reaction of 513 with DDAH

    Scheme 63

    Scheme 63. Metabolism of 4-Chloropyridine-Based Spectinamide Derivatives 516 Catalyzed by GST

    Scheme 64

    Scheme 64. Postulated Mechanism of Inactivation of Tyrosine Hydroxylase by 550 and 551

    Scheme 65

    Scheme 65. Base-Catalyzed Reaction (Path a) and Trytophanase-Mediated Metabolism (Path b) of 552

    Scheme 66

    Scheme 66. Mechanism-Based Inactivation of Neuraminidases by Sialoside Substrates Bearing Difluoromethylphenol Groups

    Figure 13

    Figure 13. Design of the fluorescent probe 561 for assessment of galactosidase activity.

    Scheme 67

    Scheme 67. Mechanism-Based Labeling of a Galactosidase by the Fluorescent Reagent 561

    Scheme 68

    Scheme 68. Mechanism of Base-Catalyzed Hydrolysis of Difluoromethylimidazoles 566 and 567 to Afford the Corresponding Aldehydes 570 and 571

    Scheme 69

    Scheme 69. Base-Catalyzed Hydrolysis of Phenol 572 to Give the Acid 575

    Scheme 70

    Scheme 70. Mechanism of Photodegradation of the CF3 Moiety of 578

    Scheme 71

    Scheme 71. Photodegradation of 581 under Simulated Sunlight in Deionized H2O to Give the Carboxylic Acid 582

    Scheme 72

    Scheme 72. Photodegradation of 584, Which Is Produced In Vivo from the Prodrug 583

    Scheme 73

    Scheme 73. Light-Catalyzed Polymerization of 589

    Scheme 74

    Scheme 74. Use of Aryl CF3 Moieties in the Design of Latent Electrophiles, Which Can Be Generated by Irradiation with Light and Used to Covalently Modify Target Proteins

    Scheme 75

    Scheme 75. Two Potential Mechanisms for Elimination of CF3 from 604

    Scheme 76

    Scheme 76. Substituent at the 2-Position of the Quinone (Methyl or Difluoromethyl) Affects the Chemical and Biochemical Pharmacological Profile of Antischistosomal Compounds

    Scheme 77

    Scheme 77. Mechanism of Inhibition of Thymidylate Synthase by 614, the Monophosphate Metabolite of 613

    Scheme 78

    Scheme 78. Oxidative Metabolism of the CF3S Substituent of 624 in RLM and Rats to Afford the Sulfoxides 626 and 627 and Sulfone 628a

    aThe absolute configurations of the sulfoxides 626 and 627 were not determined, and the assignments shown are arbitrary.

    Scheme 79

    Scheme 79. Substituent Effects on Phospholipase A2 Suicide Inhibition by 633

    Scheme 80

    Scheme 80. Metabolism of the [(Fluoromethyl)thio]carbonyl Moiety of 145 by P450 to Afford the Carboxylic Acid 638
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